This patent application is a continuation-in-part of Eckstein et al., U.S. Ser. No. 09/444,209 filed Nov. 19, 1999, which is a continuation-in-part of Eckstein et al., U.S. Ser. No. 09/159,274 filed Sep. 22, 1998, now U.S. Pat. No. 6,127,173 which claims the benefit of Eckstein et al., U.S. Ser. No. 60/059,473 filed Sep. 22, 1997, all entitled “NUCLEIC ACID CATALYSTS WITH ENDONUCLEASE ACTIVITY”. Each of these applications is hereby incorporated by reference herein in its entirety including the drawings.

The Sequence Listing file named “MBHB00,884-C SequenceListing.txt” (313,506 bytes in size) submitted on Compact Disc-Recordable (CD-R) medium (entitled “010810 — 1001”) in compliance with 37 C.F.R. § 1.52(e) is incorporated herein by reference.

›BACKGROUND OF THE INVENTION · 1 of 2

This invention relates to nucleic acid molecules with catalytic activity and derivatives thereof.

The following is a brief description of enzymatic nucleic acid molecules. This summary is not meant to be complete but is provided only for understanding of the invention that follows. This summary is not an admission that all of the work described below is prior art to the claimed invention.

Enzymatic nucleic acid molecules (ribozymes) are nucleic acid molecules capable of catalyzing one or more of a variety of reactions, including the ability to repeatedly cleave other separate nucleic acid molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be used, for example, to target virtually any RNA transcript (Zaug et al., 324 , Nature 429 1986; Cech, 260 JAMA 3030, 1988; and Jefferies et al., 17 Nucleic Acids Research 1371, 1989).

Because of their sequence-specificity, trans-cleaving enzymatic nucleic acid molecules show promise as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem . 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem . 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the mRNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited.

There are seven basic varieties of naturally occurring enzymatic RNAs. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets.

In addition, several in vitro selection (evolution) strategies (Orgel, 1979 , Proc. R. Soc. London , B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing a variety of reactions, such as cleavage and ligation of phosphodiester linkages and amide linkages, (Joyce, 1989 , Gene , 82, 83-87; Beaudry et al., 1992 , Science 257, 635-641; Joyce, 1992 , Scientific American 267, 90-97; Breaker et al., 1994 , TIBTECH 12, 268; Bartel et al., 1993 , Science 261:1411-1418; Szostak, 1993 , TIBS 17, 89-93; Kumar et al, 1995 , FASEB J ., 9, 1183; Breaker, 1996 , Curr. Op. Biotech ., 7, 442).

The enzymatic nature of a ribozyme is advantageous over other technologies, since the effective concentration of ribozyme necessary to effect a therapeutic treatment is generally lower than that of an antisense oligonucleotide. This advantage reflects the ability of the ribozyme to act enzymatically, Thus, a single ribozyme (enzymatic nucleic acid) molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding, but also on the mechanism by which the molecule inhibits the expression of the RNA to which it binds. That is, the inhibition is caused by cleavage of the RNA target and so specificity is defined as the ratio of the rate of cleavage of the targeted RNA over the rate of cleavage of non-targeted RNA. This cleavage mechanism is dependent upon factors additional to those involved in base pairing. Thus, it is thought that the specificity of action of a ribozyme is greater than that of antisense oligonucleotide binding the same RNA site.

The development of ribozymes that are optimal for catalytic activity would contribute significantly to any strategy that employs RNA-cleaving ribozymes for the purpose of regulating gene expression. The hammerhead ribozyme functions with a catalytic rate (k cat ) of ˜1 min −1 in the presence of saturating (10 mM) concentrations of Mg 2+ cofactor. However, the rate for this ribozyme in Mg 2+ concentrations that are closer to those found inside cells (0.5-2 mM) can be 10- to 100-fold slower. In contrast, the RNase P holoenzyme can catalyze pre-tRNA cleavage with a k cat of ˜30 min −1 under optimal assay conditions. An artificial ‘RNA ligase’ ribozyme has been shown to catalyze the corresponding self-modification reaction with a rate of ˜100 min −1 . In addition, it is known that certain modified hammerhead ribozymes that have substrate binding arms made of DNA catalyze RNA cleavage with multiple turn-over rates that approach 100 min −1 . Finally, replacement of a specific residue within the catalytic core of the hammerhead with certain nucleotide analogues gives modified ribozymes that show as much as a 10-fold improvement in catalytic rate. These findings demonstrate that ribozymes can promote chemical transformations with catalytic rates that are significantly greater than those displayed in vitro by most natural self-cleaving ribozymes. It is then possible that the structures of certain self-cleaving ribozymes may be optimized to give maximal catalytic activity, or that entirely new RNA motifs can be made that display significantly faster rates for RNA phosphodiester cleavage.

An extensive array of site-directed mutagenesis studies have been conducted with the hammerhead ribozyme to probe relationships between nucleotide sequence and catalytic activity. These systematic studies have made clear that most nucleotides in the conserved core of the hammerhead ribozyme cannot be mutated without significant loss of catalytic activity. In contrast, a combinatorial strategy that simultaneously screens a large pool of mutagenized ribozymes for RNAs that retain catalytic activity could be used more efficiently to define immutable sequences and to identify new ribozyme variants. Although similar in vitro selection experiments have been conducted with the hammerhead ribozyme (Nakamaye & Eckstein, 1994 , Biochemistry 33, 1271; Long & Uhlenbeck, 1994 , Proc. Natl. Acad. Sci ., 91, 6977; Ishizaka et al., 1995 , BBRC 214, 403; Vaish et al., 1997 , Biochemistry 36, 6495), none of these efforts have successfully screened full-sized hammerhead ribozymes for all possible combinations of sequence variants that encompass the entire catalytic core.

›BACKGROUND OF THE INVENTION · 2 of 2

The hammerhead ribozyme is one of the smallest ribozymes known and has thus attracted much attention for the study of structure-function relationships in catalytic. RNAs as well as for its potential for the sequence-specific inhibition of gene expression (Usman et al., supra). The hammerhead cleaves RNA sequence-specifically adjacent to the general triplet sequence NUX, where N is any nucleotide and X can be A, U or C. Cleavage behind a guanosine such as in GUG is very slow (4.3×10 −5 min −1 ) compared to the triplet substrate GUC (1 min −1 ) (Baidya et al., 1997 , Biochemistry 36, 1108). Although the X-ray structure of this ribozyme has been solved and a mechanism proposed (Pley et al., 1994 Nature , 372, 68; Scott et al., 1996 , Science 274, 2065), the question of what determines its specificity for the NUX sequence is still largely unresolved. One way of obtaining an insight into this problem might be to compare sequences of hammerhead ribozymes with different triplet cleaving specificities. In previous publications, it was demonstrated, using in vitro selection, that the native hammerhead sequence necessary to cleave a typical cleavage triplet, NUX, can not be altered (Nakamaye & Eckstein, 1994 , Biochemistry 33, 1271; Long & Uhlenbeck, 1994 , Proc. Natl. Acad. Sci ., 91, 6977; Ishizaka et al., 1995 , BBRC 214, 403; Vaish et al., 1997 , Biochemistry 36, 6495), indicating that nature has evolved a close to perfect GUC cleaver. It was of interest to see what changes have to be imposed on the native hammerhead sequence for it to cleave after AUG, which usually resists cleavage, and thus arrive at a ribozyme with a new specificity. To achieve this, an in vitro selection was undertaken, where the number of randomized positions in the starting pool corresponded to the number of nucleotides typically found in the core and stem-loop II region of a hammerhead ribozyme. This would allow all possible sequence permutations to be explored in the search for a hammerhead which is able to cleave behind AUG (Robertson & Joyce, 1990 , Nature 344:6265 467-8; Ellington and Szostak, 1990; Tuerk & Gold, 1990; Wright & Joyce, 1997; Carmi et al., 1997; for reviews see Breaker, 1997; Abelson, 1996; Ellington, 1997; Chapman & Szostak, 1994). Tang et al., 1997, RNA 3, 914, reported novel ribozyme sequences with endonuclease activity, where the authors used an in vitro selection approach to isolate these ribozymes.

The platelet derived growth factor (PDGF) system has served as a prototype for the identification of substrates of receptor tyrosine kinases. Certain enzymes become activated by the PDGF receptor kinase, including phospholipase C and phosphatidylinositol 3′ kinase, Ras guanosine triphosphate (GTPase) activating protein (GAP) and src-like tyrosine kinases. GAP regulates the function of the Ras protein. It stimulates the GTPase activity of the 21 kD Ras protein (Barbacid. 56 Ann. Rev. Biochem . 779, 1987). Microinjection of oncogenically activated Ras into NIH 3T3 cells induces DNA synthesis. Mutations that cause oncogenic activation of ras lead to accumulation of Ras bound to GTP, the active form of the molecule. These mutations block the ability of GAP to convert Ras to the inactive form. Mutations that impair the interactions of Ras with GAP also block the biological function of Ras.

While a number of ras alleles exist (N-ras, K-ras, H-ras) which have been implicated in carcinogenesis, the type most often associated with colon and pancreatic carcinomas is the K-ras. Ribozymes which are targeted to certain regions of the K-ras allelic mRNAs may also prove inhibitory to the function of the other allelic mRNAs of the N-ras and H-ras genes.

Transformation is a cumulative process whereby normal control of cell growth and differentiation is interrupted, usually through the accumulation of mutations affecting the expression of genes that regulate cell growth and differentiation.

Scanlon WO91/18625, WO91/18624, and WO91/18913 describe a specific hammerhead ribozyme effective to cleave RNA from the H-ras gene at codon 12 mutation. This ribozyme is said to inhibit H-ras expression in response to exogenous stimuli.

Thompson et al., U.S. Pat. Nos. 5,610,052 and 5,801,158, describes enzymatic RNA molecules against Ras.

Vaish et al., 1998 PNAS 95, 2158-2162, describes the in vitro selection of a hammerhead-like ribozyme with an extended range of cleavable triplets.

The references cited above are distinct from the presently claimed invention since they do not disclose and/or contemplate the catalytic nucleic acid molecules of the instant invention.

›SUMMARY OF THE INVENTION · 1 of 3

This invention relates to novel nucleic acid molecules with catalytic activity, which are particularly useful for cleavage of RNA or DNA. The nucleic acid catalysts of the instant invention are distinct from other nucleic acid catalysts known in the art. The nucleic acid catalysts of the instant invention do not share sequence homology with other known ribozymes. Specifically, nucleic acid catalysts of the instant invention are capable of catalyzing an intermolecular or intramolecular endonuclease reaction.

In a preferred embodiment, the invention features a nucleic acid molecule with catalytic activity having one of the formulae I-V:

In each of the above formulae, N represents independently a nucleotide or a non-nucleotide linker, which may be the same or different; X and Y are independently oligonucleotides of length sufficient to stably interact (e.g., by forming hydrogen bonds with complementary nucleotides in the target) with a target nucleic acid molecule (the target can be an RNA, DNA or RNA/DNA mixed polymers); m and n are integers independently greater than or equal to 1 and preferably less than about 100, wherein if (N) m and (N) n are nucleotides, (N)m and (N)n are optionally able to interact by hydrogen bond interaction; J is an oligonucleotide of length 6 or 7 nucleotides; K is an oligonucleotide of length 5 nucleotides; L is a linker which may be present or absent (i.e., the molecule is assembled from two separate molecules), but when present, is a nucleotide and/or a non-nucleotide linker, which may be a single-stranded and/or double-stranded region; and ——— represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage or others known in the art). Z is independently a nucleotide numbered as 13.1 (FIG. 8) which can stably interact with a nucleotide at position 14.1 (FIG. 8) in the target nucleic acid molecule, preferably, the N 13.1 -N 14.1 interaction is inosine 13.1 -cytidine 14.1 ; adenosine 13.1 -uridine 14.1 ; guanosine 13.1 -cytidine 14.1 ; uridine 13.1 -adenosine 14.1 ; or cytidine 13.1 -guanosine 14.1 ; and C, G, A, and U represent cytidine, guanosine, adenosine and uridine nucleotides, respectively. The nucleotides in the each of the formulae I-V are unmodified or modified at the sugar, base, and/or phosphate as known in the art.

In a preferred embodiment, the invention features nucleic acid molecules of Formula I, where the sequence of oligonucleotide J is selected from the group comprising 5′-GGCAUCC-3′, 5′-AGCAUU-3′, 5′-GCAUCA-3′, 5′-AGCAUC-3′, and 5′-AGCGUC-3′.

In another preferred embodiment, the invention features nucleic acid molecules of Formula II, where the sequence of oligonucleotide J is 5′-GGAAUC-3′.

In a further preferred embodiment, the invention features nucleic acid molecules of Formula III, where the sequence of oligonucleotide K is selected from the group comprising 5′-UGAUG-3′, 5′-UGAUC-3′, and 5′-UGGGC-3′.

In another embodiment, the nucleotide linker (L) is a nucleic acid sequence selected from the group consisting of 5′-GCACU-3′, 5′-GAACU-3′, 5′-GCACC-3′, 5′-GNACU-3′, 5′-GNGCU-3′, 5′-GNCCU-3′, 5′-GNUCU-3′, 5′-GNGUU-3′, 5′-GNCUU-3′, 5′-GNUUU-3′, 5′-GNAUU-3′, 5′-GNACA-3′, 5′-GNGCA-3′, 5′-GNCCA-3′, and 5′-GNUCA-3′, whereby N can be selected from the group consisting of A, G, C, or U.

In yet another embodiment, the nucleotide linker (L) is a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995 , Annu. Rev. Biochem ., 64, 763; and Szostak & Ellington, 1993, in The RNA World , ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A “nucleic acid aptamer” as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.

In yet another embodiment, the non-nucleotide linker (L) is as defined herein. The term “non-nucleotide” as used herein include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res . 1990, 18:6353 and Nucleic Acids Res . 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc . 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc . 1991, 113:5109; Ma et al., Nucleic Acids Res . 1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res . 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett . 1993, 34:301; Ono et al.; Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc . 1991, 113:4000, all hereby incorporated by reference herein. Thus, in a preferred embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule. By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenine, guanine, cytosine, uracil or thymine. The terms “abasic” or “abasic nucleotide” as used herein encompass sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position.

In preferred embodiments, the enzymatic nucleic acid includes one or more stretches of RNA, which provide the enzymatic activity of the molecule, linked to the non-nucleotide moiety. The necessary RNA components are known in the art (see for e.g., Usman et al., supra). By RNA is meant a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” is meant a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribo-furanose moiety.

›SUMMARY OF THE INVENTION · 2 of 3

Thus, in one preferred embodiment, the invention features ribozymes that inhibit gene expression and/or cell proliferation. These chemically or enzymatically synthesized nucleic acid molecules contain substrate binding domains that bind to accessible regions of specific target nucleic acid molecules. The nucleic acid molecules also contain domains that catalyze the cleavage of target. Upon binding, the enzymatic nucleic acid molecules cleave the target molecules, preventing, for example, translation and protein accumulation. In the absence of the expression of the target gene, cell proliferation, for example, is inhibited. In another aspect of the invention, enzymatic nucleic acid molecules that cleave target molecules are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described below, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors can be repeatedly administered as necessary. Once expressed, the ribozymes cleave the target mRNA. Delivery of ribozyme expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review, see, Couture and Stinchcomb, 1996 , TIG ., 12, 510).

As used in herein “cell” is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human. The cell may be present in a non-human multicellular organism, e.g., birds, plants and mammals such as cows, sheep, apes, monkeys, swine, dogs, and cats.

In a preferred embodiment, an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid catalysts of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid catalyst of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

In one embodiment, the expression vector comprises: a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said gene is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

By “patient” is meant an organism which is a donor or recipient of explanted cells or the cells themselves. “Patient” also refers to an organism to which enzymatic nucleic acid molecules can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells.

By “vectors” is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

Another means of accumulating high concentrations of a ribozyme(s) within cells is to incorporate the ribozyme-encoding sequences into a DNA or RNA expression vector. Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase. I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 Proc. Natl. Acad. Sci. USA , 87, 6743-7; Gao and Huang 1993 Nucleic Acids Res ., 21, 2867-72; Lieber et al., 1993 Methods Enzymol ., 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol ., 10, 4529-37). Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA , 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Yu et al., 1993 Proc. Natl. Acad. Sci. USA , 90, 6340-4; L'Huillier et al., 1992 EMBO J . 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U. S. A ., 90, 8000-4; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Sullenger & Cech, 1993 , Science 262, 1566). The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).

In another preferred embodiment, catalytic activity of the molecules described in the instant invention can be optimized as described by Draper et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms, or chemically synthesizing ribozymes with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases and/or enhance their enzymatic activity (see e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314; Usman and Cedergren, 1992 Trends in Biochem. Sci . 17, 334; Usman et. al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5;334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications to the molecules, which enhance their efficacy in cells, and removal of bases from stem loop structures to shorten RNA synthesis times and reduce chemical requirements are desired. All these publications are hereby incorporated by reference herein.

›SUMMARY OF THE INVENTION · 3 of 3

By “enhanced enzymatic activity” is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both catalytic activity and ribozyme stability. In this invention, the product of these properties is increased or not significantly (less than 10-fold) decreased in vivo compared to an all RNA ribozyme.

In yet another preferred embodiment, nucleic acid catalysts having chemical modifications, which maintain or enhance enzymatic activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. As exemplified herein, such ribozymes are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al., 1996 , Biochemistry , 35, 14090). Such ribozymes herein are said to “maintain” the enzymatic activity of an all RNA ribozyme.

In yet another aspect the invention features an enzymatic nucleic acid molecule which cleaves mRNA produced from the human K-ras gene (accession NM — 004985), H-ras gene (accession NM — 005343) or N-ras gene (accession NM — 002524). In one nonlimiting example, the enzymatic nucleic acid molecule of the present invention cleaves mRNA molecules associated with the development or maintenance of colon carcinoma. In preferred embodiments, the enzymatic nucleic acid molecules comprise sequences which are complementary to the substrate sequences in Table II. Examples of such enzymatic nucleic acid molecules also are shown in Table II. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in Table II.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

›DESCRIPTION OF THE PREFERRED EMBODIMENTS

The drawings will first briefly be described.

›DRAWINGS

FIG. 1 A) is a diagrammatic representation of the hammerhead ribozyme domain known in the art. Stem II can be 2 base-pairs long. Each N is independently any base or non-nucleotide as used herein; B) is a diagrammatic representation of a self-cleaving hammerhead ribozyme; C) is a diagrammatic representation of a random pool of self-cleaving RNA. N indicates the region with random nucleotides. (SEQ ID NO: 1171-1174)

FIG. 2 is a schematic representation of a non-limiting in vitro selection strategy used to evolve nucleic acid catalysts. (SEQ ID NO: 1175-1189)

FIG. 3 shows sequences of individual RNAs that represent new classes of self-cleaving ribozymes. Also shown are rates of catalysis (k in-cis (min −1 )) for each of the new self-cleaving RNA sequences. The underlined sequences indicate the regions capable of interacting with each other. (SEQ ID NO: 1175-1189)

FIG. 4 summarizes structure mapping studies on clone 40 RNA. (SEQ ID NO: 1190)

FIG. 5 shows sequence and possible secondary structure of a trans-cleaving ribozyme of the invention. Arrow identifies the site of cleavage. (SEQ ID NO: 1191-1192)

FIG. 6 shows non-limiting examples of trans-cleaving ribozyme-substrate complex of the present invention. (SEQ ID NO: 1193-1198)

FIG. 7 shows non-limiting examples of chemically modified trans-cleaving ribozyme-substrate complex of the present invention. (SEQ ID NO: 1199-1206)

FIG. 8 shows a non-limiting example of a chemically modified trans-cleaving ribozyme-substrate complex of the present invention and the numbering system used for (SEQ ID NO: 1207-1208)

›NUCLEIC ACID CATALYSTS · 1 of 7

The invention provides nucleic acid catalysts and methods for producing a class of enzymatic nucleic acid cleaving agents which exhibit a high degree of specificity for the nucleic acid sequence of a desired target. The enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of a target such that specific diagnosis and/or treatment of a disease or condition in a variety of biological system can be provided with a single enzymatic nucleic acid. Such enzymatic nucleic acid molecules can be delivered exogenously to specific cells as required. In the preferred hammerhead motif, the small size (less than 60 nucleotides, preferably between 30-40 nucleotides in length) of the molecule allows the cost of treatment to be reduced.

By “nucleic acid catalyst” as used herein is meant a nucleic acid molecule (e.g., the molecule of formulae I-V), capable of catalyzing (altering the velocity and/or rate of) a variety of reactions including the ability to repeatedly cleave other separate nucleic acid molecules (endonuclease activity) in a nucleotide base sequence-specific manner. Such a molecule with endonuclease activity may have complementarity in a substrate binding region (e.g. X and Y in formulae I-V) to a specified-gene target, and also has an enzymatic activity that specifically cleaves RNA or DNA in that target. That is, the nucleic acid molecule with endonuclease activity is able to intramolecularly or intermolecularly cleave RNA or DNA and thereby inactivate a target RNA or DNA molecule. This complementarity functions to allow sufficient hybridization of the enzymatic RNA molecule to the target RNA or DNA to allow the cleavage to occur. 100% complementarity is preferred, but complementarity as low as 50-75% may also be useful in this invention. The nucleic acids may be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, nucleozyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, oligozyme, finderon or nucleic acid catalyst. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific examples of enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule.

By “nucleic acid molecule” as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and may comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

By “complementarity” is meant that a nucleic acid can form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well-known in the art (see, e.g., Turner et al., 1987 , CSH Symp. Quant. Biol . LII pp.123-133; Frier et al., 1986 , Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987 , J. Am. Chem. Soc . 109:3783-3785. A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

The enzymatic nucleic acid molecules of Formulae I-V may independently comprise a cap structure which may independently be present or absent.

By “sufficient length” is meant an oligonucleotide of greater than or equal to 3 nucleotides. For example, for the X and Y portions of the nucleic acid molecules disclosed in formulae I-V “sufficient length” means that the nucleotide length is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the X and Y portions are not so long as to prevent useful turnover.

By “stably interact” is meant, interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions).

By “chimeric nucleic acid molecule” or “mixed polymer” is meant that, the molecule may be comprised of both modified or unmodified nucleotides.

By “cap structure” is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide. These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. The cap may be present at the 5′-terminus. (5′-cap) or at the 3′-terminus (3′-cap) or may be present on both termini. In non-limiting examples: the 5′-cap is selected from the group comprising inverted abasic residue (moiety); 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Beigelman et al., International PCT publication No. WO 97/26270, incorporated by reference herein).

›NUCLEIC ACID CATALYSTS · 2 of 7

In yet another preferred embodiment the 3′-cap is selected from a group comprising, 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5′-mercapto moieties (for more details, see, Beaucage and Iyer, 1993 , Tetrahedron 49, 1925; incorporated by reference herein).

By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. The terms “abasic” or “abasic nucleotide” as used herein encompass sugar moieties lacking a base or having other chemical groups in place of base at the 1′ position.

By “oligonucleotide” as used herein, is meant a molecule comprising two or more nucleotides.

The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site (e.g., X and Y of Formulae I-V above) which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule.

By “enzymatic portion” is meant that part of the ribozyme essential for cleavage of an RNA substrate.

By “substrate binding arm” or “substrate binding domain” is meant that portion of a ribozyme which is complementary to (i.e., able to base-pair with) a portion of its substrate. Generally, such complementarity is 100%, but can be less if desired. For example, as few as 10 nucleotides out of a total of 14 may be base-paired. Such arms are shown generally in FIG. 1 A and as X and Y in Formulae I-V. That is, these arms contain sequences within a ribozyme which are intended to bring ribozyme and target RNA together through complementary base-pairing interactions. The ribozyme of the invention may have binding arms that are contiguous or non-contiguous and may be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides; specifically 12-100 nucleotides; more specifically 14-24 nucleotides long. The two binding arms are chosen, such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, six and six nucleotides or seven and seven nucleotides long) or asymmetrical (i e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

Catalytic activity of the ribozymes described in the instant invention can be optimized as described by Draper et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms, or chemically synthesizing ribozymes with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases and/or enhance their enzymatic activity (see e.g. Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314, Usman and Cedergren, 1992 Trends in Biochem. Sci . 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications which enhance their efficacy in cells, and removal of bases from stem loop structures to shorten RNA synthesis times and reduce chemical requirements are desired. All these publications are hereby incorporated by reference herein.

Therapeutic ribozymes must remain stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, ribozymes must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA (Wincott et al., 1995 Nucleic Acids Res . 23, 2677; incorporated by reference herein) have expanded the ability to modify ribozymes to enhance their nuclease stability. The term “nucleotide” is used as recognized in the art to include natural bases, and modified bases well known in the art. Such bases are generally located at the 1′ position of a sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; all hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art. These recently have been summarized by Limbach et al., 1994 , Nucleic Acids Res . 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into enzymatic nucleic acids without significantly effecting their catalytic activity include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyluracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine) and others (Burgin et al., 1996 , Biochemistry , 35, 14090). By “modified bases” in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases may be used within the catalytic core of the enzyme and/or in the substrate-binding regions.

›NUCLEIC ACID CATALYSTS · 3 of 7

In a preferred embodiment, the invention features modified ribozymes with phosphate backbone modifications comprising one or.more phosphorothioate and/or phosphorodithioate substitutions. A non-limiting, preferred example of a ribozyme of the instant invention utilizing phosphorothioate and/or phosphorodithioate modifications in conjunction with 2′-O-methyl ribonucleotides and conserved ribonucleotide residues is shown in FIG. 8 . The incorporation of phosphorothioate and/or phosphorodithioate linkages into the enzymatic nucleic acid of the instant invention results in increased serum stability. Replacement of the 3′-phosphodiester at position 6 with a phosphorothioate or phosphorodithioate linkage (FIG. 8) stabilizes the conserved position 6 ribose moiety, which is prone to nucleolytic cleavage. In a study investigating the serum stability of position 6 modified ribozyme variants which preserve the 2′-hydroxyl function at position 6 (FIG. 8 ), the relative stability of the modifications were ranked as follows:

3′-Phosphorodithioate>>3′-Phosphorothioate>>4′-Thioribofuranose>Phosphodiester

The preferred incorporation of one to four, but preferably two, phosphorothioate linkages at the 5′-end of the position 6 3′-phosphorothioate ribozyme (FIG. 8) does not significantly affect the cleavage rate of the molecule. In a comparison study, the incorporation of up to four phosphorothioate residues at the 5′-end of this molecule is well tolerated. The incorporation of a 3′-phosphorodithioate residue at.position 6 of the ribozyme results in a 50% reduction in catalytic activity over the corresponding position 6 3′-phosphorothioate derivative. The loss of catalytic activity in the case of the position 6 3′-phosphorodithoate substitution may be offset by the increased serum stability that this modification offers and is likely to enhance the effectiveness of the ribozyme in cells.

In a preferred embodiment, the invention features a 3′-phosphorothioate linkage at position 6 of the nucleic acid molecule of the instant invention (FIG. 8 ).

In yet another preferred embodiment, the invention features a 3′-phosphorodithioate linkage at position 6 of the nucleic acid molecule (FIG. 8 ).

In a further preferred embodiment of the instant invention, an inverted deoxy abasic moiety is utilized at the 3′ end of the enzymatic nucleic acid molecule.

In particular, the invention features modified ribozymes having a base substitution selected from pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyluracil, dihydrouracil, naphthyl, 6-methyl-uracil and aminophenyl.

There are several examples in the art describing sugar and phosphate modifications that can be introduced into enzymatic nucleic acid molecules without significantly effecting catalysis and with significant enhancement in their nuclease stability and efficacy. Ribozymes are modified to enhance stability and/or enhance catalytic activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992 TIBS 17, 34; Usman et al., 1994 Nucleic Acids Symp. Ser . 31, 163; Burgin et al., 1996 Biochemistry 35, 14090). Sugar modifications of enzymatic nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature 1990, 344, 565-568; Pieken et al. Science 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci . 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995 J. Biol. Chem . 270, 25702).

Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid catalysts of the instant invention.

As the term is used in this application, non-nucleotide-containing enzymatic nucleic acid means a nucleic acid molecule that contains at least one non-nucleotide component which replaces a portion of a ribozyme, e.g., but not limited to, a double-stranded stem, a single-stranded “catalytic core” sequence, a single-stranded loop or a single-stranded recognition sequence. These molecules are able to cleave (preferably, repeatedly cleave) separate RNA or DNA molecules in a nucleotide base sequence specific manner. Such molecules can also act to cleave intramolecularly if that is desired. Such enzymatic molecules can be targeted to virtually any RNA transcript.

The sequences of ribozymes that are chemically synthesized, useful in this invention, are shown in Table II. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the enzymatic nucleic acid molecule (all but the binding arms) is altered to affect activity. The ribozyme sequences listed in Table II may be formed of ribonucleotides or other nucleotides or non-nucleotides. Such ribozymes with enzymatic activity are equivalent to the ribozymes described specifically in the Table.

Synthesis of Nucleic Acid Molecules

Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs (“small refers to nucleic acid motifs no more than 100 nucleotides in length, preferably no more than 80 nucleotides in length, and most preferably no more than 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the hairpin ribozymes) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention were chemically synthesized, and others can similarly be synthesized. Oligodeoxyribonucleotides were synthesized using standard protocols as described in Caruthers et al., 1992 , Methods in Enzymology 211,3-19, and is incorporated herein by reference.

›NUCLEIC ACID CATALYSTS · 4 of 7

The method of synthesis used for normal RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al., 1987 J. Am. Chem. Soc ., 109, 7845; Scaringe et al., 1990 Nucleic Acids Res ., 18, 5433; Wincott et al., 1995 Nucleic Acids Res . 23, 2677-2684; and Wincott et al., 1997 , Methods Mol. Bio ., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses were conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by calorimetric quantitation of the trityl fractions, were 97.5-99%. Other oligonucleotide, synthesis reagents for the 394 Applied . Biosystems, Inc. synthesizer; detritylation solution was 3% TCA in methylene chloride (ABI); capping was performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution was 16.9 mM I 2 , 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile was used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) was made up from the solid obtained from American International Chemical, Inc.

Deprotection of the RNA was performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20° C., the supernatant was removed from the polymer support. The support was washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant was then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, were dried to a white powder. The base deprotected oligoribonucleotide was resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer was quenched with 1.5 M NH 4 HCO 3 .

Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO:1/1 (0.8 mL) at 65° C. for 15 min. The vial was brought to r.t. TEA.3HF (0.1 mL) was added and the vial was heated at 65° C. for 15 min. The sample was cooled at −20° C. and then quenched with 1.5 M NH 4 HCO 3 .

For purification of the trityl-on oligomers, the quenched NH 4 HCO 3 solution was loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA was detritylated with 0.5% TFA for 13 min. The cartridge was then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide was then eluted with 30% acetonitrile.

Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides) were synthesized by substituting a U for G 5 and a U for A 14 (numbering from Hertel, K. J., et al., 1992 , Nucleic Acids Res ., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

The average stepwise coupling yields were >98% (Wincott et al., 1995 Nucleic Acids Res . 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96-well format, all that is important is the ratio of chemicals used in the reaction.

Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992 , Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991 , Nucleic Acids Research 19, 4247; Bellon et al., 1997 , Nucleosides & Nucleotides , 16, 951; Bellon et al., 1997 Bioconjugate Chem . 8, 204).

Ribozymes of the instant invention are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989 , Methods Enzymol . 180, 51).

Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; see, Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water.

Administration of Ribozymes

Sullivan et al., PCT WO 94/02595, describes the general methods for delivery of enzymatic RNA molecules. Ribozymes may be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. For some indications, ribozymes may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the RNA/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent. Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. More detailed descriptions of ribozyme delivery and administration are provided in Sullivan et al., supra and Draper et al., PCT WO93/23569 which have been incorporated by reference herein.

›NUCLEIC ACID CATALYSTS · 5 of 7

The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

The negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention may also be formulated and used as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions for injectable administration, and other compositions known in the art.

The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, egg., acid addition salts, for example, salts of hydrochloric, hydrobromic; acetic acid, and benzene sulfonic acid.

A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example, oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching, a target cell (i e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations, such as toxicity and forms which prevent the composition or formulation from exerting its effect.

By “systemic administration” is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach may provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.

The invention also features the use of a composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev . 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull . 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995 , Biochim. Biophys. Acta , 1238, 86-90). All of these references are incorporated by reference herein. The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem . 1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen.

The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences , Mack Publishing Co. (A. R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents may be provided. Id. at 1449. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used.

A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. In a one aspect, the invention provides enzymatic nucleic acid molecules that can be delivered exogenously to specific cells as required. The enzymatic nucleic acid molecules are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to smooth muscle cells. The RNA or RNA complexes can be locally administered to relevant tissues through the use of a catheter, infusion pump or stent, with or without their incorporation in biopolymers. Using the methods described herein, other enzymatic nucleic acid molecules that cleave target nucleic acid may be derived and used as described above. Specific examples of nucleic acid catalysts of the instant invention are provided below in the Tables and figures.

›NUCLEIC ACID CATALYSTS · 6 of 7

Alternatively, the enzymatic nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985 Science 229, 345; McGarry and Lindquist, 1986 Proc. Natl. Acad. Sci. USA 83, 399; Scanlon et al., 1991 , Proc. Natl. Acad. Sci. USA , 88, 10591-5; Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Dropulic et al., 1992 J. Virol , 66, 1432-41; Weerasinghe et al., 1991 J. Virol , 65, 5531-4; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Sarver et al., 1990 Science 247, 1222-1225; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Good et al., 1997 , Gene Therapy, 4, 45; all of the references are hereby incorporated by reference herein in their totalities). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a ribozyme (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992 Nucleic Acids Symp. Ser ., 27, 15-6; Taira et al., 1991 , Nucleic Acids Res ., 19, 5125-30; Ventura et al., 1993 Nucleic Acids Res ., 21, 3249-55; Chowrira et al., 1994 J. Biol. Chem . 269, 25856; all of the references are hereby incorporated by reference herein in their totalities).

In another aspect of the invention, enzymatic nucleic acid molecules that cleave target molecules are expressed from transcription units (see, for example, Couture et al., 1996 , TIG ., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors might be repeatedly administered as necessary. Once expressed, the ribozymes cleave the target mRNA. The active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind target nucleic acid molecules such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage. Delivery of ribozyme expressing vectors could be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review, see Couture et al., 1996 , TIG ., 12, 510).

In one aspect, the invention features, an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid catalysts of the instant invention. The nucleic acid sequence encoding the nucleic acid catalyst of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

In another aspect the invention features, an expression vector comprising: a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g. eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′ side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the, nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 Proc. Natl. Acad. Sci. USA , 87, 6743-7; Gao and Huang 1993 Nucleic Acids Res ., 21, 2867-72; Lieber et al., 1993 Methods Enzymol ., 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol ., 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA , 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Yu et al., 1993 Proc. Natl. Acad. Sci. USA , 90, 6340-4; L'Huillier et al., 1992 EMBO J . 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U.S.A ., 90, 8000-4; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Sullenger & Cech, 1993 , Science , 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994 , Nucleic Acid Res ., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997 , Gene Ther . 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein). Examples of transcription units suitable for expression of ribozymes of the instant invention are shown in FIG. 15 . The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review, see Couture and Stinchcomb, 1996, supra).

›NUCLEIC ACID CATALYSTS · 7 of 7

In yet another aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the catalytic nucleic acid molecules of the invention, in-a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In another preferred embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a sequence encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3′-end of said open reading frame; and wherein said gene is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

By “consists essentially of” is meant that the active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind target nucleic acid molecules such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage.

›EXAMPLES

The following are non-limiting examples showing the selection, isolation, synthesis and activity of enzymatic nucleic acids of the instant invention.

An extensive array of site-directed mutagenesis studies have been conducted with the hammerhead to probe relationships between nucleotide sequence and catalytic activity. These systematic studies have made clear that most nucleotides in the conserved core of the hammerhead ribozyme (Forster & Symons, 1987 , Cell , 49, 211) cannot be mutated without significant loss of catalytic activity. In contrast, a combinatorial strategy that simultaneously screens a large pool of mutagenized ribozymes for RNAs that retain catalytic activity could be used more efficiently to define immutable sequences and to identify new ribozyme variants (Breaker, 1997, supra). For example, Joseph and Burke (1993 ; J. Biol. Chem ., 268, 24515) have used an in vitro selection approach to rapidly screen for sequence variants of the ‘hairpin’ self-cleaving RNA that show improved catalytic activity. This approach was successful in identifying two mutations in the hairpin ribozyme that together give a 10-fold improvement in catalytic rate. Although similar in vitro selection experiments have been conducted with the hammerhead ribozyme (Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra), none of these efforts have successfully screened full-sized hammerhead ribozymes for all possible combinations of sequence variants that encompass the entire catalytic core.

Applicant employed in vitro selection strategy to comprehensively test whether the natural consensus sequence for the core of the hammerhead ribozyme produces maximal catalytic rates, or whether sequence variants of this ribozyme could catalyze endonuclease reaction similar to or better than the hammerhead ribozyme.

The procedure reported herein to select for intramolecular AUG cleaving sequences is based on Applicant's previously reported selection of alternative GUC cleaving hammerhead sequences (Vaish et al., 1997 , Biochemistry 36, 6495; incorporated by reference herein).

›Examples13

›Example 1 · 1 of 2

In Vitro Selection of Self-cleaving RNAs From a Random Pool

An initial pool of dsDNAs containing 22 randomized positions flanked by two constant regions was synthesized. These were transcribed, with transcription being initiated with GTPγS, to produce a pool of potential ribozymes. Self-cleavage of active ribozymes occurs during transcription and the cleavage products can then be separated from intact transcripts by means of a mercury gel (Igloi, Biochemistry 27, 3842). The recovered cleavage products were then reverse transcribed and amplified by PCR to give a dsDNA pool of selected ribozymes. This selection procedure was repeated for 13 cycles before the dsDNA pool was cloned and sequenced.

Oligodeoxyribonucleotides and oligoribonucleotides were chemically synthesized and purified as previously described (Vaish et al., 1997 Biochemistry 36, 6495). Primers used in the selection:

Primer 1:

5′-TGGTGCAAGCTT AATACGACTCACTATA GGGAGACTGTCTAGATCATGAGGATGCTA-3′(Seq. ID No. 1167);

Primer 2:

5′-TCTCGGATCCTGCAGATCATNNNNNNNNNNNNNNNNNNNNNNAGGATTAGCATCCTCAT-3′(Seq. ID No. 1168).

These two primers were used for the initial Sequenase® reaction, and Primer 2 also functioned as restoration primer for the reintroduction of the lost sequences during cleavage. Reverse transcription (RT)-Primer, 5′-TCTCGGATCCTGCAGATCAT-3′ (Seq. ID No. 1169); and polymerase chain reaction (PCR)-Primer, 5′-TGGTGCAAGCTT AATACGACTCA -3′ (Seq. ID No. 1170), with HindIII (5′-end) and BamHI and PstI (3′-end) sites in boldface; T7 promoter is underlined; ribozyme cleavage triplet in italics; N, randomized nucleotides. RNA selection was performed as described (Vaish et al., 1997 Biochemistry 36, 6495 incorporated by reference herein) with modifications to the initial two cycles of selection. Transcriptions from Pool 0 and Pool 1 were performed on a larger scale (10×500 μl and 1×250 μl, respectively) for 12 h and PCR amplification (Step 5) was omitted in each case. Successive transcriptions were performed at 100 μl volume. Transcription reactions were for decreasing periods of time from 12 h (1 st cycle) to 1 min (13 th cycle), where reactions for short periods were quenched by addition of EDTA (75 mM final conc.). All transcriptions were performed with 1 μM DNA. DNA template in the PCR mixture was at least 1×10 −15 M. The minimum concentration of RNA template was 1×10 −8 M for reverse transcription. The concentrations were determined assuming a molar extinction coefficient of 6600.

A selection pressure was exerted by progressively reducing the time of transcription from 12 h for the first six cycles, to 6 h for the seventh, 1 h for the eighth, 30 min for the ninth and tenth, 5 min for the eleventh, and 1 min for the twelve and thirteenth cycle. White colonies were randomly selected from pools 7 and 10 and those showing self-cleavage upon transcription were sequenced. There was no homology among the sequences.

Cloning and sequencing was performed as described (Vaish et al., 1997 , Biochemistry 36, 6495) except that the dsDNA was digested with HindIII and BamHI. Clones from pools seven and ten were tested for transcript self-cleavage from linearized plasmids. For clones from Pool 13 plasmid DNA was amplified by PCR, using the RT- and PCR-primers, and then transcribed. Rates of intramolecular cleavage of transcripts were determined as described but with 10 u of enzyme per μl. Active clones were sequenced. A transcript of only 50 nucleotides, without the extra sequences for cloning beyond stem III, showed a k in-cis of 0.32 min −1 .

By “randomized region” is meant a region of completely random sequence and/or partially random sequence. By completely random sequence is meant a sequence wherein theoretically there is equal representation of A, T, G and C nucleotides or modified derivatives thereof, at each position in the sequence. By partially random sequence is meant a sequence wherein there is an unequal representation of A, T, G and C nucleotides or modified derivatives thereof, at each position in the sequence. A partially random sequence can therefore have one or more positions of complete randomness and one or more positions with defined nucleotides.

Characterization of New Self-cleaving Ribozyme Sequences

The intramolecular cleavage rate of the most active sequence of pool 7 was 0.03 min −1 and that of pool 10 was 0.06 min −1 (FIG. 3 ). Seventy clones from pool thirteen were picked and amplified by PCR. Of these, 20 gave full-length DNA and were transcribed; and, of these, 14 showed intramolecular cleavage. These 14 active ribozymes could be divided into two groups: one group contained transcripts with 22 nucleotides in the randomized region and the second group contained a deletion in this region with only 21 nucleotides being present. Several sequences were represented twice such as those of clones 29, 36 and 40. One of the most active sequences, from clone 13/40, with k in-cis of 0.52 min −1 was chosen for further study. In comparison, under these conditions the intramolecular cleavage of the native hammerhead with a GUC triplet was k in-cis of 0.56 min −1 , indicating that the cleavage activity of the selected ribozyme, Rz13/40, with an AUG triplet is comparable. In order to acquire some information on the secondary structure of Rz13/40, a limited nuclease digest of the 3′-end-labeled, full-length ribozyme was performed. Rz13/40 was prepared by transcription in such a way that cleavage was minimized. A full length transcript for the intramolecularly cleaving ribozyme was generated by transcription at 12° C. for 8 h (Frank et al., 1996 , RNA , 2, 1179; incorporated by reference herein) and 3′-end labeled with 32 pCp. Limited nuclease digestions with RNase A, RNase T1 and nuclease S1 were performed as Hodson et al., 1994 , Nucleic Acids Res ., 22, 1620; Loria et al., 1996 , RNA , 2,551; both are incorporated by reference herein). Alkaline hydrolysis of labeled RNA was performed in 50 mM NaHCO 3 at 100° C. for 7.5 minutes.

Limited digestion with RNase A and T1 and nuclease S1, which indicates single-stranded regions, gave a digestion pattern consistent with Rz13/40 adopting a hammerhead-type structure, which comprised three base-paired helices surrounding a single-stranded core (FIG. 4 ). Since the structure of Rz13/40 resembles the hammerhead structure, the same numbering system has been adopted, with positions 3 and 9 in the core being considered vacant.

›Example 1 · 2 of 2

The data of nuclease digestion corresponded fairly well with the MFOLD structure except for a few discrepancies. MFOLD shows base pairing in the core region between U 7 and G 14 ; G 8 and C 13 ; G L2.1 and U L2.5 ; and U 4 and G 7 although there cleavage at these positions by the nucleases.

Ribozyme Engineering

Sequence, chemical and structural variants of ribozymes of the present invention can be engineered using the techniques shown above and known in the art to cleave a separate target RNA or DNA in trans . For example, the size of ribozymes can, be reduced or increased using the techniques known in the art (Zaug et al., 1986 , Nature , 324, 429; Ruffner et al., 1990 , Biochem ., 29, 10695; Beaudry et al., 1990 , Biochem ., 29, 6534; McCall el al., 1992 , Proc. Natl. Acad. Sci., USA ., 89, 5710; Long et al., 1994, Supra; Hendry et al., 1994 , BBA 1219, 405; Benseler et al., 1993 , JACS , 115, 8483; Thompson et al., 1996 , Nucl. Acids Res ., 24, 4401; Michels et al., 1995 , Biochem ., 34, 2965; Been et al., 1992 , Biochem ., 31, 11843; Guo et al., 1995 , EMBO. J ., 14, 368; Pan et al., 1994 , Biochem ., 33, 9561; Cech, 1992 , Curr. Op. Struc. Bio., 2 , 605 ; Sugiyama et al., 1996 , FEBS Lett ., 392, 215; Beigelman et al., 1994 , Bioorg. Med. Chem ., 4, 1715; all are incorporated in its totality by reference herein). For example, the stem-loop II domain of the ribozymes may not be essential for catalytic activity and hence could be systematically reduced in size using a variety of methods known in the art, to the extent that the overall catalytic activity of the ribozyme is not significantly decreased.

Further rounds of in vitro selection strategies described herein and variations thereof can be readily used by a person skilled in the art to evolve additional nucleic acid catalysts and such new catalysts are within the scope of the instant invention.

›Example 2 · 1 of 2

Trans-cleaving Ribozymes

The self-cleaving ribozymes can be divided into separate ribozyme and substrate domains to create a functional bimolecular complex. This ribozyme presumably interacts with the substrate domain by forming base-paired regions that arc analogous to helices I and II of the hammerhead ribozyme (FIG. 1 ). Likewise, the substrate specificity of ribozymes can presumably be altered by changing the sequences of the substrate-binding arms to complement the sequence of the desired substrate molecule, as was achieved with the ribozyme from clone 40 self-cleaving RNA (FIG. 5 ). The numbering convention used in Example 2 is taken from Vaish et al., 1998 PNAS 95, 2158-2162.

To further characterize the selected ribozyme for intermolecular cleavage, Rz13/40 was divided into a catalytic portion and the corresponding substrate strand (FIG. 5 ). The initial ribozyme construct was designed with 5 bp each in stems I and III for annealing to the substrate. Stems of this length were chosen because they had been reported to give reliable kinetic data with the hammerhead. Cleavage kinetics of intramolecularly cleaving ribozymes was performed with chemically synthesized ribozyme and substrate in 50 mM Tris-HCl (pH 8.0), and 10 mM MgCl 2 with 50 to 500 nM ribozyme and 25 nM substrate for single turnover, and 50 to 500 nM substrate with 5 to 25 nM ribozyme for multiple turnover kinetics as described (Hertel et al., Biochemistry 33, 3374, 1994). The intermolecular version of Rz13/40 of the present invention gave a very high K M (1.1 mM) and low k cat (0.1 min −1 ) under single turnover conditions and was inactive under multiple turnover conditions. As there was no doubt about the intramolecular cleavage of Rz13/40, the lack of catalytic activity under multiple turnover conditions must be associated with the design of the intermolecular version. After analysis of the ribozyme-substrate complex by native gel, it was concluded that formation of the complex was inefficient under the conditions used.

A second ribozyme construct was synthesized, where stem III was extended to 10 base-pairs. Native gel analysis confirmed the formation of the ribozyme-substrate complex and the ribozyme cleaved its corresponding substrate efficiently under both single and multiple turnover conditions (Table III). The discrepancy between kcat and kcat′ (0.06 and 0.91 min −1 respectively) is presumably the result of product inhibition, which is a common effect observed with the native hammerhead. The time course of cleavage was followed for about 12 half-lives under single turnover conditions. Reactions were first order up to 60% cleavage within the first minute and reached a total of 80%. First order end points with the conventional hammerhead are commonly 70 to 75%. Steady state cleavage rates were linear for several turnovers. Although the hammerhead and class I ribozymes cleave at different internucleotide linkages (FIG. 1 ), both ribozymes appear to proceed by a similar chemical mechanism. The hammerhead ribozyme is known to produce a 2′,3′-cyclic phosphate at the terminus of the 5′-cleavage product, thereby leaving a 5′-hydroxyl terminus on the 3′-cleavage fragment.

The site of substrate cleavage was confirmed as being behind G of the AUG cleavage triplet by comparison of the ribozyme cleavage product, obtained under single turnover conditions for 30 min, with the products of a limited alkaline hydrolysis of the 5′-end-labeled substrate and with a partial RNase T1 digest. Reactions were performed in 10 μl containing RNA, 50 mM Tris (pH 8) and CNPase (Sigma Chemicals) (0.62 u to 0.012 u/μl) and incubation at 45° C. for 1.5 h. Product analysis was on a 20% PAGE where the cyclic phosphate-terminated product runs slightly slower than the ring-opened derivative. In addition, the cleavage products were also shown to be the 2′, 3′-cyclic phosphate and a 5′-hydroxyl by hydrolysis with CNPase and labeling with T4 PNK respectively. Thus Rz13/40 cleaves in a similar manner to the hammerhead. In order to investigate the properties and sequence requirements of the selected ribozyme Rz13/40, mutations were made on the substrate and ribozyme strands. In the native hammerhead, stem II has been shortened to as few as two base-pairs without significant loss in activity. However, the removal of a single base-pair (10.3/11.3) in Rz13/40 resulted in a 1000-fold loss in activity for the cleavage behind an AUG triplet indicating the stem-loop structure has a wider role in catalysis.

The effect of mutations around the cleavage site has also been investigated under single and multiple turnover conditions (Table III). Surprisingly, the AUA triplet was also cleaved quite efficiently even though it was not selected for, again yielding a 2′, 3′-cyclic phosphate. Triplets terminating in a uridine or cytidine were either cleaved extremely slowly or not at all. Thus, this ribozyme is purine nucleoside specific. Whether this indicates a necessity for base pairing between U 4 and the nucleotide to be cleaved, as possible with AUG and AUA, is uncertain at present.

As the native hammerhead strictly requires a uridine in the middle of the triplet, it was of interest to test whether this was applicable to Rz13/40. Interestingly the triplet AAG was cleaved with a k cat of 0.57 min −1 under single turnover conditions, multiple turnover conditions showed a k cat of 0.09 min −1 . It was also tested whether the nucleotide next to the cleavage site was of importance. Cleavage of the triplet AUG followed by U or G was found to be only fractionally slower in single turnover than cleavage of AUG-A (Table III).

Inspection of the ribozyme sequences reveals some interesting features. The sequence 5′-GCGCG at positions 11.2 to 14 is present in all ribozymes from pool 10 onwards. This would indicate that this sequence may be an indispensable part for activity just as is the case for the GAA sequence in the conventional hammerhead.

Of the two classes of ribozyme isolated in Pool 13, the ribozymes with a deletion in the randomized region.are the more active intramolecular cleavers. These ribozymes appear to have an overall secondary structure which is similar to that of the native hammerhead, but there are significant differences.

›Example 2 · 2 of 2

Obvious differences include the ‘vacancies’ at positions 3 and 9 in the core as well as the altered sequence to positions 12 to 14 of the traditional hammerhead ribozyme (FIG. 1) already mentioned. More subtle differences are associated with stem-loop II. In the hammerhead, a variety of structures are tolerated: the stem can be reduced to two base-pairs, and the loop can be of virtually any size and even contain non-nucleotidic linkers. In the selected ribozymes similar to Rz13/40, less variation in the stem-loop structure is observed. In the active ribozymes of this class, the stem-loop II consists of two G:C base-pairs adjacent to the core which are followed by two A:U base-pairs. The stem loop terminates in a five nucleotide loop, where variations at only positions L2.4 and L2.5 of the hammerhead ribozyme have been detected. The length of the stem appears to have a large effect on catalytic efficiency, since the removal of a single base-pair (10.3/11.3) abolishes activity in vitro. The most active sequences in pool 13 have a fully complementary stem II. One mismatch at 10.2/11.2 as in Rz13/1 approximately halves the activity. It is interesting to note that in Pool 13, the more active ribozymes contain a deletion in the randomized region, which is 21 nucleotides instead of 22. Of these only Rz13/31 and 13/29 show reasonable activity. One can draw a secondary structure for these with a stem II with two mismatches and the extra nucleotide in the core region.

Initial experiments to determine cleavage site specificities of ribozymes of the instant invention indicate NR/N as the minimum requirement for ribozyme cleavage, where N represents any nucleotide, R represents any purine nucleotide, and / indicates the site of cleavage. Persons skilled in the art can perform further experiments to determine potential cleavage targets of the ribozymes of the instant invention, such experiments can be performed as described in Ruffner et al., 1990 , Biochem ., 29, 10695, and Joseph et al., 1993 , Genes and Development ., 7, 130-138.

The new triplet specificity should be useful for the application of the ribozyme family of the present invention for the inhibition of gene expression in that it expands the targets on a mRNA for cleavage. Although the conventional NUX triplets might be considered sufficient for a wide application, the accessibility of oligodeoxynucleotides to mRNAs is very restricted. Thus the specificity of the new ribozyme for cleavage at purines, apparently independent of the nature of the neighboring nucleotides, should represent a considerable advantage over the native NUX-cleaving ribozyme for this application.

›Example 3

Substrate Specificity Variants

An investigation of base pairs at positions 13.1-14.1 of the ribozyme shown in FIG. 9 was undertaken. Six different ribozyme-substrate combinations were synthesized where N 13.1 -N 14.1 was either adenosine 13.1 -urdine 14.1 (RZ 1), uridine 13.1 -adenosine 14.1 (RZ 2), inosine 13.1 -cytidine 14.1 (RZ 3), guanosine 13.1 -cytidine 14.1 , (Rz 4) cytidine 13.1 -guanosine 14.1 (RZ 5), or guanosine 13.1 -guanosine 14.1 (RZ 6). The time course of the cleavage of ribozymes 3-6 in FIG. 9 with non A-U base pairs was determined (FIG. 10 ). As shown in FIG. 10, no significant difference was observed between cleavage rates of ribozyme substrate complexes containing the I 13.1 -C 14.1 or G 13.1 -C 14.1 base pair (0.29 vs. 0.21 min −1 , FIG. 10 ). Under comparable conditions the cleavage rate of the AUG substrate was 0.1min −1 with the 6 bp stem III and 5 bp stem I ribozyme (Vaish et al., 1998 PNAS 95, 2158-2162).

Because the A 13.1 -U 14.1 pair can be inverted t U 13.1 -A 14.1 without loss of activity (Example 2 above) it was of interest to study Ribozyme-Substrate complexes containing the C 13.1 -G 14.1 pair (RZ 5). This inverted C 13.1 -G 14.1 arrangement retains significant activity (0.09 min −1 ), and it is only 3-fold less active than the corresponding G-C base pair. The use of a G-G base pair (RZ 6) under the specific conditions used in the example caused a significant reduction in the activity of the ribozyme. The A 13.1 -U 14.1 pair containing ribozyme-substrate complex can cleave a target after an AU 14.1 G triplet; specificity of this ribozyme can be altered to cleave after AG 14.1 G triplets with a G 13.1 to C 13.1 substitution. The AU 14.1 G triplet recognizing ribozyme can therefore be engineered to cleavage after AA 14.1 G (see, Example 2), AC 14.1 G and AG 14.1 G triplets.

Since the original AU 14.1 G cleaving ribozymes have nonspecific requirements for the 1.1 nucleotide (i.e. the nucleotide downstream of G15) and since position 15 may be any purine, the experimental evidence for the acceptance of any nucleoside at the 14.1 position indicates NR 15 /N as the minimum requirement for ribozyme cleavage, where N represents any nucleotide, R represents any purine nucleotide, and / indicates the site of cleavage. The optimization of these variant ribozyme constructs by modification of stem-loop structures as is known in the art can provide for species with improved cleavage activity.

›Example 4

Identification of Potential Target Sites in Human K-ras RNA

The sequence of human K-ras was screened for accessible sites using a computer folding algorithm selecting for AUR/, YG/M, and UG/U target sites where R in any purine, Y is any pyrimidine, M is A or C, and A, U, C, G are adenosine, uridine, cytidine, and guanosine, respectively. Regions of the RNA that did not form secondary folding structures and included cleavage sites for the ribozymes of the instant invention were identified. The sequences of these cleavage sites are shown in Table II.

›Example 5

Selection of Enzymatic Nucleic Acid Cleavage Sites in Human K-ras RNA

To test whether the sites predicted by the computer-based RNA-folding algorithm corresponded to accessible sites in K-ras RNA ninety-six ribozyme sites from Table II were selected for further analysis. Ribozyme target sites were chosen by analyzing sequences of Human K-ras, (accession number: NM — 004985) and prioritizing the sites on the basis of folding. Ribozymes were designed that could bind each target and were individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol. Struc. Theochem , 311, 273; Jaeger et al., 1989 , Proc. Natl. Acad. Sci. USA , 86, 7706) to assess whether the ribozyme sequences fold into the appropriate secondary structure. Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core were eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

›Example 6

Chemical Synthesis and Purification of Ribozymes for Efficient Cleavage of K-ras RNA

Ribozymes were designed to anneal to various sites in the RNA message. The binding arms are complementary to the target site sequences described above. The ribozymes were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem. Soc ., 109, 7845), Scaringe et al., (1990 Nucleic Acids Res ., 18, 5433) and Wincott et al., supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. The average stepwise coupling yields were >98%.

On instrument dithioate linkage formation via PADS/3-picoline: All processes were performed on an ABI (PE Biosystems) 394 DNA/RNA Synthesizer. Phosphorodithioate containing ribozymes were synthesized using PADS (Phenoxy acetyl disulfide), 3-Picoline, Acetonitrile, 5′-O-DMT-2′-O-TBDMS-Uridine-3′-thiophosphoramidite, and standard synthesis reagents and phosphoramidites. A 0.2 M solution of PADS was prepared in 1:1 acetonitrile:3-picoline. This solution was placed on the instrument and substituted for the normal oxidizing reagent to create the phosphorodithioate triester bond. The thio-amidite (0.1 M in ACN) was coupled for 450 seconds using a standard cycle. At the oxidation step, the PADS solution was delivered for 7.5s at a flow rate of 5 mL/min. and with a 300s wait time after delivery. After completion of the synthesis, the oligo was deprotected and purified in the standard manner (MA/H 2 O, 3HF.TEA, NH 4 HCO 3 quench, T-on solid phase purification).

›Example 7

Ribozyme Cleavage of K-ras RNA Target in Vitro

Ribozymes targeted to the human K-ras RNA are designed and synthesized as described above. These ribozymes can be tested for cleavage activity in vitro, for example using the following procedure. The target sequences and the nucleotide location within the K-ras RNA are given in Table II.

Cleavage Reactions: Full-length or partially full-length, intemally-labeled target RNA for ribozyme cleavage assay is prepared by in vitro transcription in the presence of [α- 32 p] CTP, passed over a G 50 Sephadex® column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl 2 ) and the cleavage reaction was initiated by adding the 2× ribozyme mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37° C. using a final concentration of either 40 nM or 1 mM ribozyme, i.e., ribozyme excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95° C. for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by ribozyme cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.

›Example 8

Cleavage Reactions for Determining Substrate Specificity of Stabilized Ribozymes (Table IV)

Substrates are 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 8.0 at 37° C., 10 mM MgCl 2 ) and the cleavage reaction is initiated by adding the 2× ribozyme mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. Assays are carried out for 1 hour at 37° C. using a final concentration of 500 nM ribozyme, i.e., ribozyme excess. The reaction is quenched at specific time points by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the time points are heated to 95° C. for 1 minute and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by ribozyme cleavage are visualized by scanning a Phosphor Imager® screen which has been exposed to the assay gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products. Table IV lists the substrate specificity rate constants for stabilized G-cleaver Ribozymes.

›Example 9

Ribozyme Stability Assay

A mixture of 1.5 μg 5′- 32 P-end labeled ribozyme and 13 μg unlabeled (cold) ribozyme is dried down and resuspended in 20 μL human serum. The suspension is incubated at 37° C. for 24 hours. Aliquots of the reaction are quenched at specific time points by removal into a 2.5-fold excess of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol on ice. A portion of each time point is counted on a scintillation counter for normalizing counts per lane. The time points are heated to 95° C. for 1 minute and loaded onto a denaturing polyacrylamide gel at 750 k cpm per lane. Intact ribozyme and the specific RNA degradation products generated by exposure to ribonucleases in the serum are visualized by scanning a Phosphor Imager® screen which has been exposed to the assay gel. The percentage of full-length ribozyme at each time point is determined by Phosphor Imager® quantitation of bands representing the intact ribozyme and the degradation products. A non-limiting example of a ribozyme of the instant invention utilizing phosphorothioate and/or phosphorodithioate modifications in a stabilized 2′-O-methyl ribonucleotide background with essential “core ribonucleotides” is shown in FIG. 8 . The incorporation of phosphorothioate and/or phosphorodithioate linkages into the enzymatic nucleic acid of the instant invention results in increased serum stability. Replacement of the 3′-phosphodiester at position 6 with a phosphorothioate or phosphorodithioate linkage (FIG. 8) stabilizes the conserved position 6 ribose moiety, which is prone to nucleolytic cleavage. In a study investigating the serum stability of position 6 modified ribozyme variants which preserve the 2′-hydroxyl function at position 6 (FIG. 8 ), the relative stability of the modifications were ranked as follows:

3′-Phosphorodithioate>>3′-Phosphorothioate>>4′-Thioribofuranose>Phosphodiester

›Example 10 · 1 of 2

Cell Culture Models

A selected group of 96 G-cleaver ribozymes targeting K-ras RNA (Table V) were tested in human colorectal cancer cells with a mutated K-ras allele (DLD-1), ovarian cancer cells with a mutated K-ras allele (SKOV3), and human colorectal cancer cells with a mutated K-ras allele (SW680). Cells were plated into four 96 well plates at 15000 cells/well. The 96 ribozymes were split into four groups (on four plates) to be able to include the appropriate controls on each plate. The ribozymes were transfected at 100 nM concentration with 5 μg/ml of GSV and incubated overnight Total RNA was prepared 24 hr after transfection using a Quiagen 96 well Rneasy® kit. An additional DNaseI treatment to remove traces of DNA was introduced. RT reactions were prepared using 4 μl of the RNA eluate with a Clontech RT-kit. Analyses were performed using a Multiplex Taqman® assay(PE ABI Prism® 7700 Sequence Detection System User Bulletin #5, © Copyright 1998, The Perkin-Elmer Corporation) using actin as a control. Results indicate that ribozyme (RPI No. 12819, Table V) reduced K-ras mRNA levels by 50% in DLD-1 cells and SKOV3 cells.

Diagnostic Uses

Enzymatic nucleic acids of this invention may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of target RNA in a cell. The close relationship between ribozyme activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple ribozymes described in this invention, one may map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with ribozymes may be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets may be defined as important mediators of the disease. These experiments will lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes and/or other chemical or biological molecules). Other in vitro uses of ribozymes of this invention are well known in the art, and include detection of the presence of mRNAs associated with disease condition. Such RNA is detected by determining the presence of.a cleavage product after treatment with a ribozyme using standard methodology.

In a specific example, ribozymes which can cleave only wild-type or mutant forms of the target RNA are used for the assay. The first ribozyme is used to identify wild-type RNA present in the sample and the second ribozyme will be used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA will be cleaved by both ribozymes to demonstrate the relative ribozyme efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species. The cleavage products from the synthetic substrates will also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus, each analysis can involve two ribozymes, two substrates and one unknown sample which will be combined into six reactions. The presence of cleavage products will be determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios will be correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.

Additional Uses

Potential usefulness of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem . 44:273). For example, the pattern of restriction fragments could be used to establish sequence relationships between two related RNAs, and large RNAs could be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the ribozyme is ideal for cleavage of RNAs of unknown sequence.

All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

›Example 10 · 2 of 2

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terns and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

Thus, additional embodiments are within the scope of the invention and within the following claims.

ggcggcggcc gcggcg 16

›RNA

Homo sapiens

uggcggcggc gaaggu 16

›RNA

Homo sapiens

cccggccccc gccauu 16

›RNA

Homo sapiens

gacugggagc gagcgc 16

›RNA

Homo sapiens

gggagcgagc gcggcg 16

›RNA

Homo sapiens

cgagcgcggc gcaggc 16

›RNA

Homo sapiens

cgcaggcacu gaaggc 16

›RNA

Homo sapiens

gcucccaggu gcggga 16

›RNA

Homo sapiens

agagaggccu gcugaa 16

›RNA

Homo sapiens

gaggccugcu gaaaau 16

›RNA

Homo sapiens

ugcugaaaau gacuga 16

›RNA

Homo sapiens

gaaaaugacu gaauau 16

›RNA

Homo sapiens

augacugaau auaaac 16

›RNA

Homo sapiens

gacugaauau aaacuu 16

›RNA

Homo sapiens

auauaaacuu guggua 16

›RNA

Homo sapiens

guuggagcuu guggcg 16

›RNA

Homo sapiens

aggcaagagu gccuug 16

›RNA

Homo sapiens

agagugccuu gacgau 16

›RNA

Homo sapiens

gugccuugac gauaca 16

›RNA

Homo sapiens

ccuugacgau acagcu 16

›RNA

Homo sapiens

gaaucauuuu guggac 16

›RNA

Homo sapiens

uuuuguggac gaauau 16

›RNA

Homo sapiens

guggacgaau augauc 16

›RNA

Homo sapiens

ggacgaauau gaucca 16

›RNA

Homo sapiens

auccaacaau agagga 16

›RNA

Homo sapiens

aguaguaauu gaugga 16

›RNA

Homo sapiens

aguaauugau ggagaa 16

›RNA

Homo sapiens

ggagaaaccu gucucu 16

›RNA

Homo sapiens

ucucuuggau auucuc 16

›RNA

Homo sapiens

ggauauucuc gacaca 16

›RNA

Homo sapiens

ggaguacagu gcaaug 16

›RNA

Homo sapiens

acagugcaau gaggga 16

›RNA

Homo sapiens

accaguacau gaggac 16

›RNA

Homo sapiens

ggcuuucuuu guguau 16

›RNA

Homo sapiens

cuuucuuugu guauuu 16

›RNA

Homo sapiens

uuguguauuu gccaua 16

›RNA

Homo sapiens

uauuugccau aaauaa 16

›RNA

Homo sapiens

ugccauaaau aauacu 16

›RNA

Homo sapiens

cauaaauaau acuaaa 16

›RNA

Homo sapiens

uaaaucauuu gaagau 16

›RNA

Homo sapiens

auuugaagau auucac 16

›RNA

Homo sapiens

ucaccauuau agagaa 16

›RNA

Homo sapiens

uaaggacucu gaagau 16

›RNA

Homo sapiens

cucugaagau guaccu 16

›RNA

Homo sapiens

auguaccuau gguccu 16

›RNA

Homo sapiens

aguaggaaau aaaugu 16

›RNA

Homo sapiens

ggaaauaaau gugauu 16

›RNA

Homo sapiens

aaauaaaugu gauuug 16

›RNA

Homo sapiens

aaugugauuu gccuuc 16

›RNA

Homo sapiens

aagaaguuau ggaauu 16

›RNA

Homo sapiens

uccuuuuauu gaaaca 16

›RNA

Homo sapiens

aagacagggu guugau 16

›RNA

Homo sapiens

acaggguguu gaugau 16

›RNA

Homo sapiens

ggguguugau gaugcc 16

›RNA

Homo sapiens

uguugaugau gccuuc 16

›RNA

Homo sapiens

ugccuucuau acauua 16

›RNA

Homo sapiens

acauuaguuc gagaaa 16

›RNA

Homo sapiens

cgagaaauuc gaaaac 16

›RNA

Homo sapiens

ucgaaaacau aaagaa 16

›RNA

Homo sapiens

aagaaaagau gagcaa 16

›RNA

Homo sapiens

gagcaaagau gguaaa 16

›RNA

Homo sapiens

aagacaaagu guguaa 16

›RNA

Homo sapiens

gacaaagugu guaauu 16

›RNA

Homo sapiens

guguaauuau guaaau 16

›RNA

Homo sapiens

uuauguaaau acaauu 16

›RNA

Homo sapiens

aauacaauuu guacuu 16

›RNA

Homo sapiens

cuuaaggcau acuagu 16

›RNA

Homo sapiens

gguaauuuuu guacau 16

›RNA

Homo sapiens

auuagcauuu guuuua 16

›RNA

Homo sapiens

uuuuuuuccu gcucca 16

›RNA

Homo sapiens

ccugcuccau gcagac 16

›RNA

Homo sapiens

caugcagacu guuagc 16

›RNA

Homo sapiens

uaccuuaaau gcuuau 16

›RNA

Homo sapiens

auuuuaaaau gacagu 16

›RNA

Homo sapiens

uuuuuuccuc gaagug 16

›RNA

Homo sapiens

uccucgaagu gccagu 16

›RNA

Homo sapiens

uuugguuuuu gaacua 16

›RNA

Homo sapiens

aacuagcaau gccugu 16

›RNA

Homo sapiens

agcaaugccu gugaaa 16

›RNA

Homo sapiens

caaugccugu gaaaaa 16

›RNA

Homo sapiens

aaaagaaacu gaauac 16

›RNA

Homo sapiens

gaaacugaau accuaa 16

›RNA

Homo sapiens

uaagauuucu gucuug 16

›RNA

Homo sapiens

gguuuuuggu gcaugc 16

›RNA

Homo sapiens

uuuggugcau gcaguu 16

›RNA

Homo sapiens

gcaugcaguu gauuac 16

›RNA

Homo sapiens

cuuaccaagu gugaau 16

›RNA

Homo sapiens

uaccaagugu gaaugu 16

›RNA

Homo sapiens

aagugugaau guuggu 16

›RNA

Homo sapiens

gaauguuggu gugaaa 16

›RNA

Homo sapiens

auguuggugu gaaaca 16

›RNA

Homo sapiens

acaaauuaau gaagcu 16

›RNA

Homo sapiens

ugaagcuuuu gaauca 16

›RNA

Homo sapiens

ucccuauucu guguuu 16

›RNA

Homo sapiens

ccuauucugu guuuua 16

›RNA

Homo sapiens

cuagucacau aaaugg 16

›RNA

Homo sapiens

ucacauaaau ggauua 16

›RNA

Homo sapiens

aauuucaguu gagacc 16

›RNA

Homo sapiens

gguuuuuacu gaaaca 16

100

›RNA

Homo sapiens

100

cugaaacauu gaggga 16

101

›RNA

Homo sapiens

101

acaaauuuau gggcuu 16

102

›RNA

Homo sapiens

102

ugggcuuccu gaugau 16

103

›RNA

Homo sapiens

103

gcuuccugau gaugau 16

104

›RNA

Homo sapiens

104

uccugaugau gauucu 16

105

›RNA

Homo sapiens

105

uaggcaucau guccua 16

106

›RNA

Homo sapiens

106

cauguccuau aguuug 16

107

›RNA

Homo sapiens

107

ccuauaguuu gucauc 16

108

›RNA

Homo sapiens

108

ugucaucccu gaugaa 16

109

›RNA

Homo sapiens

109

caucccugau gaaugu 16

110

›RNA

Homo sapiens

110

ccugaugaau guaaag 16

111

›RNA

Homo sapiens

111

aaguuacacu guucac 16

112

›RNA

Homo sapiens

112

caaagguuuu gucucc 16

113

›RNA

Homo sapiens

113

ccuuuccacu gcuauu 16

114

›RNA

Homo sapiens

114

uauuagucau ggucac 16

115

›RNA

Homo sapiens

115

uccccaaaau auuaua 16

116

›RNA

Homo sapiens

116

aaaauauuau auuuuu 16

117

›RNA

Homo sapiens

117

uuuuuucuau aaaaag 16

118

›RNA

Homo sapiens

118

agaaaaaaau ggaaaa 16

119

›RNA

Homo sapiens

119

acaaggcaau ggaaac 16

120

›RNA

Homo sapiens

120

aaacuauuau aaggcc 16

121

›RNA

Homo sapiens

121

cacauuagau aaauua 16

122

›RNA

Homo sapiens

122

aaauuacuau aaagac 16

123

›RNA

Homo sapiens

123

gacuccuaau agcuuu 16

124

›RNA

Homo sapiens

124

gcuuuuuccu guuaag 16

125

›RNA

Homo sapiens

125

gacccaguau gaaugg 16

126

›RNA

Homo sapiens

126

caguaugaau gggauu 16

127

›RNA

Homo sapiens

127

ggauuauuau agcaac 16

128

›RNA

Homo sapiens

128

uuggggcuau auuuac 16

129

›RNA

Homo sapiens

129

auauuuacau gcuacu 16

130

›RNA

Homo sapiens

130

aaauuuuuau aauaau 16

131

›RNA

Homo sapiens

131

uuuuuauaau aauuga 16

132

›RNA

Homo sapiens

132

uauaauaauu gaaaag 16

133

›RNA

Homo sapiens

133

uaacaaguau aaaaaa 16

134

›RNA

Homo sapiens

134

aaauucucau aggaau 16

135

›RNA

Homo sapiens

135

ggaauuaaau guaguc 16

136

›RNA

Homo sapiens

136

uagucucccu guguca 16

137

›RNA

Homo sapiens

137

gucucccugu gucaga 16

138

›RNA

Homo sapiens

138

gugucagacu gcucuu 16

139

›RNA

Homo sapiens

139

gcucuuucau aguaua 16

140

›RNA

Homo sapiens

140

uucauaguau aacuuu 16

141

›RNA

Homo sapiens

141

ucuucaacuu gagucu 16

142

›RNA

Homo sapiens

142

uugagucuuu gaagau 16

143

›RNA

Homo sapiens

143

cuuugaagau aguuuu 16

144

›RNA

Homo sapiens

144

uuuuaauucu gcuugu 16

145

›RNA

Homo sapiens

145

aauucugcuu gugaca 16

146

›RNA

Homo sapiens

146

uucugcuugu gacauu 16

147

›RNA

Homo sapiens

147

ggccaguuau agcuua 16

148

›RNA

Homo sapiens

148

cuuauuaggu guugaa 16

149

›RNA

Homo sapiens

149

auuagguguu gaagag 16

150

›RNA

Homo sapiens

150

gaccaagguu gcaagc 16

151

›RNA

Homo sapiens

151

gccaggcccu guguga 16

152

›RNA

Homo sapiens

152

caggcccugu gugaac 16

153

›RNA

Homo sapiens

153

ggcccugugu gaaccu 16

154

›RNA

Homo sapiens

154

ugugaaccuu gagcuu 16

155

›RNA

Homo sapiens

155

gagcuuucau agagag 16

156

›RNA

Homo sapiens

156

uucacagcau ggacug 16

157

›RNA

Homo sapiens

157

agcauggacu gugugc 16

158

›RNA

Homo sapiens

158

cauggacugu gugccc 16

159

›RNA

Homo sapiens

159

uggacugugu gcccca 16

160

›RNA

Homo sapiens

160

acggucaucc gagugg 16

161

›RNA

Homo sapiens

161

ccgagugguu guacga 16

162

›RNA

Homo sapiens

162

gugguuguac gaugca 16

163

›RNA

Homo sapiens

163

guuguacgau gcauug 16

164

›RNA

Homo sapiens

164

agucaaaaau ggggag 16

165

›RNA

Homo sapiens

165

caguuuggau agcuca 16

166

›RNA

Homo sapiens

166

ucaacaagau acaauc 16

167

›RNA

Homo sapiens

167

aucucacucu guggug 16

168

›RNA

Homo sapiens

168

uggugguccu gcugac 16

169

›RNA

Homo sapiens

169

ugguccugcu gacaaa 16

170

›RNA

Homo sapiens

170

caagagcauu gcuuuu 16

171

›RNA

Homo sapiens

171

cauugcuuuu guuucu 16

172

›RNA

Homo sapiens

172

acuuuuaaau auuaac 16

173

›RNA

Homo sapiens

173

cucaaaaguu gagauu 16

174

›RNA

Homo sapiens

174

gggugguggu gugcca 16

175

›RNA

Homo sapiens

175

gugguggugu gccaag 16

176

›RNA

Homo sapiens

176

uuuaaacaau gaagug 16

177

›RNA

Homo sapiens

177

acaaugaagu gaaaaa 16

178

›RNA

Homo sapiens

178

aauuaacauu gcauaa 16

179

›RNA

Homo sapiens

179

aacauugcau aaacac 16

180

›RNA

Homo sapiens

180

uuucaagucu gaucca 16

181

›RNA

Homo sapiens

181

ucugauccau auuuaa 16

182

›RNA

Homo sapiens

182

cauauuuaau aaugcu 16

183

›RNA

Homo sapiens

183

auuuaauaau gcuuua 16

184

›RNA

Homo sapiens

184

gcuuuaaaau aaaaau 16

185

›RNA

Homo sapiens

185

aaauaaaaau aaaaac 16

186

›RNA

Homo sapiens

186

caauccuuuu gauaaa 16

187

›RNA

Homo sapiens

187

uccuuuugau aaauuu 16

188

›RNA

Homo sapiens

188

aauuuaaaau guuacu 16

189

›RNA

Homo sapiens

189

auuuuaaaau aaauga 16

190

›RNA

Homo sapiens

190

uaaaauaaau gaagug 16

191

›RNA

Homo sapiens

191

uaaaugaagu gagaug 16

192

›RNA

Homo sapiens

192

gaagugagau ggcaug 16

193

›RNA

Homo sapiens

193

gagauggcau ggugag 16

194

›RNA

Homo sapiens

194

auggcauggu gaggug 16

195

›RNA

Homo sapiens

195

auggugaggu gaaagu 16

196

›RNA

Homo sapiens

196

ggacuagguu guuggu 16

197

›RNA

Homo sapiens

197

gguuguuggu gacuua 16

198

›RNA

Homo sapiens

198

gguucuagau aggugu 16

199

›RNA

Homo sapiens

199

cuagauaggu gucuuu 16

200

›RNA

Homo sapiens

200

uuaggacucu gauuuu 16

201

›RNA

Homo sapiens

201

cucugauuuu gaggac 16

202

›RNA

Homo sapiens

202

auuucuucau guuaaa 16

203

›RNA

Homo sapiens

203

uuuacacuau gugauu 16

204

›RNA

Homo sapiens

204

uacacuaugu gauuua 16

205

›RNA

Homo sapiens

205

ugugauuuau auucca 16

206

›RNA

Homo sapiens

206

ccauuuacau aaggau 16

207

›RNA

Homo sapiens

207

acauaaggau acacuu 16

208

›RNA

Homo sapiens

208

acacuuauuu gucaag 16

209

›RNA

Homo sapiens

209

agcacaaucu guaaau 16

210

›RNA

Homo sapiens

210

uuuaaccuau guuaca 16

211

›RNA

Homo sapiens

211

caucuucagu gccagu 16

212

›RNA

Homo sapiens

212

gggcaaaauu gugcaa 16

213

›RNA

Homo sapiens

213

gcaaaauugu gcaaga 16

214

›RNA

Homo sapiens

214

ugcaagaggu gaaguu 16

215

›RNA

Homo sapiens

215

ugaaguuuau auuuga 16

216

›RNA

Homo sapiens

216

guuuauauuu gaauau 16

217

›RNA

Homo sapiens

217

auauuugaau auccau 16

218

›RNA

Homo sapiens

218

cuucuuccau auuagu 16

219

›RNA

Homo sapiens

219

ccauauuagu gucauc 16

220

›RNA

Homo sapiens

220

gugucaucuu gccucc 16

221

›RNA

Homo sapiens

221

ccuuccacau gcccca 16

222

›RNA

Homo sapiens

222

caugccccau gacuug 16

223

›RNA

Homo sapiens

223

cccaugacuu gaugca 16

224

›RNA

Homo sapiens

224

augacuugau gcaguu 16

225

›RNA

Homo sapiens

225

caguuuuaau acuugu 16

226

›RNA

Homo sapiens

226

uuuaauacuu guaauu 16

227

›RNA

Homo sapiens

227

cccuaaccau aagauu 16

228

›RNA

Homo sapiens

228

aagauuuacu gcugcu 16

229

›RNA

Homo sapiens

229

auuuacugcu gcugug 16

230

›RNA

Homo sapiens

230

uacugcugcu guggau 16

231

›RNA

Homo sapiens

231

ugcuguggau aucucc 16

232

›RNA

Homo sapiens

232

auaucuccau gaaguu 16

233

›RNA

Homo sapiens

233

uuuucccacu gaguca 16

234

›RNA

Homo sapiens

234

caucagaaau gcccua 16

235

›RNA

Homo sapiens

235

aagagaaucu gacaga 16

236

›RNA

Homo sapiens

236

ucugacagau accaua 16

237

›RNA

Homo sapiens

237

cagauaccau aaaggg 16

238

›RNA

Homo sapiens

238

aaagggauuu gaccua 16

239

›RNA

Homo sapiens

239

ggugguggcu gaugcu 16

240

›RNA

Homo sapiens

240

gguggcugau gcuuug 16

241

›RNA

Homo sapiens

241

cugaugcuuu gaacau 16

242

›RNA

Homo sapiens

242

acaucucuuu gcugcc 16

243

›RNA

Homo sapiens

243

ucucuuugcu gcccaa 16

244

›RNA

Homo sapiens

244

auccauuagc gacagu 16

245

›RNA

Homo sapiens

245

acccugguau gaauag 16

246

›RNA

Homo sapiens

246

ugguaugaau agacag 16

247

›RNA

Homo sapiens

247

agaauuuaau aaagau 16

248

›RNA

Homo sapiens

248

uaauaaagau agugca 16

249

›RNA

Homo sapiens

249

uaaagauagu gcagaa 16

250

›RNA

Homo sapiens

250

gguaaucuau aacuag 16

251

›RNA

Homo sapiens

251

uaacaguaau acauuc 16

252

›RNA

Homo sapiens

252

acauuccauu guuuua 16

253

›RNA

Homo sapiens

253

aaaucuucau gcaaug 16

254

›RNA

Homo sapiens

254

uucaugcaau gaaaaa 16

255

›RNA

Homo sapiens

255

aaugaaaaau acuuua 16

256

›RNA

Homo sapiens

256

uuuaauucau gaagcu 16

257

›RNA

Homo sapiens

257

uuuuuuuggu gucaga 16

258

›RNA

Homo sapiens

258

ucagagucuc gcucuu 16

259

›RNA

Homo sapiens

259

ucucgcucuu gucacc 16

260

›RNA

Homo sapiens

260

aggcuggaau gcagug 16

261

›RNA

Homo sapiens

261

augcaguggc gccauc 16

262

›RNA

Homo sapiens

262

ucagcucacu gcaacc 16

263

›RNA

Homo sapiens

263

agguucaagc gauucu 16

264

›RNA

Homo sapiens

264

cgauucucgu gccucg 16

265

›RNA

Homo sapiens

265

ucggccuccu gaguag 16

266

›RNA

Homo sapiens

266

uuacaggcgu gugcac 16

267

›RNA

Homo sapiens

267

acaggcgugu gcacua 16

268

›RNA

Homo sapiens

268

acuaauuuuu guauuu 16

269

›RNA

Homo sapiens

269

gguuucaccu guuggc 16

270

›RNA

Homo sapiens

270

ggcuggucuc gaacuc 16

271

›RNA

Homo sapiens

271

ucgaacuccu gaccuc 16

272

›RNA

Homo sapiens

272

gaccucaagu gauuca 16

273

›RNA

Homo sapiens

273

uuggccucau aaaccu 16

274

›RNA

Homo sapiens

274

ucauaaaccu guuuug 16

275

›RNA

Homo sapiens

275

aaccuguuuu gcagaa 16

276

›RNA

Homo sapiens

276

uucagcaaau auuuau 16

277

›RNA

Homo sapiens

277

aauauuuauu gagugc 16

278

›RNA

Homo sapiens

278

uuuauugagu gccuac 16

279

›RNA

Homo sapiens

279

ccuaccagau gccagu 16

280

›RNA

Homo sapiens

280

gccagucacc gcacaa 16

281

›RNA

Homo sapiens

281

cacuggguau auggua 16

282

›RNA

Homo sapiens

282

cuggguauau gguauc 16

283

›RNA

Homo sapiens

283

caagagacau aauccc 16

284

›RNA

Homo sapiens

284

cuuagguacu gcuagu 16

285

›RNA

Homo sapiens

285

uacugcuagu gugguc 16

286

›RNA

Homo sapiens

286

aguguggucu guaaua 16

287

›RNA

Homo sapiens

287

ggucuguaau aucuua 16

288

›RNA

Homo sapiens

288

ccuuugguau acgacc 16

289

›RNA

Homo sapiens

289

uuugguauac gaccca 16

290

›RNA

Homo sapiens

290

acccagagau aacacg 16

291

›RNA

Homo sapiens

291

gagauaacac gaugcg 16

292

›RNA

Homo sapiens

292

auaacacgau gcguau 16

293

›RNA

Homo sapiens

293

uuuuaguuuu gcaaag 16

294

›RNA

Homo sapiens

294

uuuggucucu gugcca 16

295

›RNA

Homo sapiens

295

uggucucugu gccagc 16

296

›RNA

Homo sapiens

296

ccagcucuau aauugu 16

297

›RNA

Homo sapiens

297

cucuauaauu guuuug 16

298

›RNA

Homo sapiens

298

uaauuguuuu gcuacg 16

299

›RNA

Homo sapiens

299

guuuugcuac gauucc 16

300

›RNA

Homo sapiens

300

cgauuccacu gaaacu 16

301

›RNA

Homo sapiens

301

gaaacucuuc gaucaa 16

302

›RNA

Homo sapiens

302

gcuacuuuau guaaau 16

303

›RNA

Homo sapiens

303

ucacuucauu guuuua 16

304

›RNA

Homo sapiens

304

uuaaaggaau aaacuu 16

305

›RNA

Homo sapiens

305

gaauaaacuu gauuau 16

306

›RNA

Homo sapiens

306

acuugauuau auuguu 16

307

›RNA

Homo sapiens

307

ugauuauauu guuuuu 16

308

›RNA

Homo sapiens

308

uauuuggcau aacugu 16

309

›RNA

Homo sapiens

309

uggcauaacu gugauu 16

310

›RNA

Homo sapiens

310

gcauaacugu gauucu 16

311

›RNA

Homo sapiens

311

gacaauuacu guacac 16

312

›RNA

Homo sapiens

312

acauuaaggu guaugu 16

313

›RNA

Homo sapiens

313

uaagguguau gucaga 16

314

›RNA

Homo sapiens

314

uaugucagau auucau 16

315

›RNA

Homo sapiens

315

agauauucau auugac 16

316

›RNA

Homo sapiens

316

uauucauauu gaccca 16

317

›RNA

Homo sapiens

317

ugacccaaau guguaa 16

318

›RNA

Homo sapiens

318

acccaaaugu guaaua 16

319

›RNA

Homo sapiens

319

aauguguaau auucca 16

320

›RNA

Homo sapiens

320

aguuuucucu gcauaa 16

321

›RNA

Homo sapiens

321

uucucugcau aaguaa 16

322

›RNA

Homo sapiens

322

uaauuaaaau auacuu 16

323

›RNA

Homo sapiens

323

auuaaaauau acuuaa 16

324

›RNA

Homo sapiens

324

aaaaauuaau aguuuu 16

325

›RNA

Homo sapiens

325

ggguacaaau aaacag 16

326

›RNA

Homo sapiens

326

aauaaacagu gccuga 16

327

›RNA

Homo sapiens

327

aacagugccu gaacua 16

328

›RNA

Homo sapiens

328

aaacuucuau guaaaa 16

329

›RNA

Homo sapiens

329

aaaucacuau gauuuc 16

330

›RNA

Homo sapiens

330

uaugauuucu gaauug 16

331

›RNA

Homo sapiens

331

uuucugaauu gcuaug 16

332

›RNA

Homo sapiens

332

gaauugcuau gugaaa 16

333

›RNA

Homo sapiens

333

auugcuaugu gaaacu 16

334

›RNA

Homo sapiens

334

uuggaacacu guuuag 16

335

›RNA

Homo sapiens

335

uagguagggu guuaag 16

336

›RNA

Homo sapiens

336

guuaagacuu gacaca 16

337

›RNA

Homo sapiens

337

agaaagaaau ggccau 16

338

›RNA

Homo sapiens

338

aaauggccau acuuca 16

339

›RNA

Homo sapiens

339

uucaggaacu gcagug 16

340

›RNA

Homo sapiens

340

gaacugcagu gcuuau 16

341

›RNA

Homo sapiens

341

cagugcuuau gagggg 16

342

›RNA

Homo sapiens

342

augaggggau auuuag 16

343

›RNA

Homo sapiens

343

uaggccucuu gaauuu 16

344

›RNA

Homo sapiens

344

uugaauuuuu gaugua 16

345

›RNA

Homo sapiens

345

aauuuuugau guagau 16

346

›RNA

Homo sapiens

346

ugauguagau gggcau 16

347

›RNA

Homo sapiens

347

uuaccuuuau gugaac 16

348

›RNA

Homo sapiens

348

accuuuaugu gaacuu 16

349

›RNA

Homo sapiens

349

ugugaacuuu gaaugg 16

350

›RNA

Homo sapiens

350

aacuuugaau gguuua 16

351

›RNA

Homo sapiens

351

caaaagauuu guuuuu 16

352

›RNA

Homo sapiens

352

auuuguuuuu guagag 16

353

›RNA

Homo sapiens

353

uucuagaaau aaaugu 16

354

›RNA

Homo sapiens

354

agaaauaaau guuacc 16

355

›RNA

Homo sapiens

355

aaaaauccuu guugaa 16

356

›RNA

Homo sapiens

356

aauccuuguu gaaguu 16

357

›RNA

Homo sapiens

357

uaaauuacau agacuu 16

358

›RNA

Homo sapiens

358

gcauuaacau guuugu 16

359

›RNA

Homo sapiens

359

uaacauguuu guggaa 16

360

›RNA

Homo sapiens

360

guggaagaau auagca 16

361

›RNA

Homo sapiens

361

ggaagaauau agcaga 16

362

›RNA

Homo sapiens

362

gcagacguau auugua 16

363

›RNA

Homo sapiens

363

gacguauauu guauca 16

364

›RNA

Homo sapiens

364

uguaucauuu gaguga 16

365

›RNA

Homo sapiens

365

ucauuugagu gaaugu 16

366

›RNA

Homo sapiens

366

uugagugaau guuccc 16

367

›RNA

Homo sapiens

367

cuauuuaacu gaguca 16

368

›RNA

Homo sapiens

368

gagucacacu gcauag 16

369

›RNA

Homo sapiens

369

cacacugcau aggaau 16

370

›RNA

Homo sapiens

370

uaacuuuuau agguua 16

371

›RNA

Homo sapiens

371

uaucaaaacu guuguc 16

372

›RNA

Homo sapiens

372

caaaacuguu gucacc 16

373

›RNA

Homo sapiens

373

ugucaccauu gcacaa 16

374

›RNA

Homo sapiens

374

gcacaauuuu guccua 16

375

›RNA

Homo sapiens

375

uuguccuaau auauac 16

376

›RNA

Homo sapiens

376

guccuaauau auacau 16

377

›RNA

Homo sapiens

377

ccuaauauau acauag 16

378

›RNA

Homo sapiens

378

auauauacau agaaac 16

379

›RNA

Homo sapiens

379

uagaaacuuu gugggg 16

380

›RNA

Homo sapiens

380

uguggggcau guuaag 16

381

›RNA

Homo sapiens

381

guuacaguuu gcacaa 16

382

›RNA

Homo sapiens

382

caucucauuu guauuc 16

383

›RNA

Homo sapiens

383

guauuccauu gauuuu 16

384

›RNA

Homo sapiens

384

aaaacaguau auauaa 16

385

›RNA

Homo sapiens

385

aacaguauau auaacu 16

386

›RNA

Homo sapiens

386

caguauauau aacuuu 16

387

›RNA

Homo sapiens

387

aaaacuaucu gaagau 16

388

›RNA

Homo sapiens

388

auuuccauuu gucaaa 16

389

›RNA

Homo sapiens

389

aaaaaguaau gauuuc 16

390

›RNA

Homo sapiens

390

augauuucuu gauaau 16

391

›RNA

Homo sapiens

391

auuucuugau aauugu 16

392

›RNA

Homo sapiens

392

cuugauaauu guguag 16

393

›RNA

Homo sapiens

393

ugauaauugu guagug 16

394

›RNA

Homo sapiens

394

auuguguagu gaaugu 16

395

›RNA

Homo sapiens

395

uguagugaau guuuuu 16

396

›RNA

Homo sapiens

396

caguuaccuu gaaagc 16

397

›RNA

Homo sapiens

397

cuugaaagcu gaauuu 16

398

›RNA

Homo sapiens

398

cugaauuuau auuuag 16

399

›RNA

Homo sapiens

399

aguaacuucu guguua 16

400

›RNA

Homo sapiens

400

uaacuucugu guuaau 16

401

›RNA

Homo sapiens

401

cuguguuaau acugga 16

402

›RNA

Homo sapiens

402

aauacuggau agcaug 16

403

›RNA

Homo sapiens

403

uggauagcau gaauuc 16

404

›RNA

Homo sapiens

404

caugaauucu gcauug 16

405

›RNA

Homo sapiens

405

auucugcauu gagaaa 16

406

›RNA

Homo sapiens

406

uugagaaacu gaauag 16

407

›RNA

Homo sapiens

407

gaaacugaau agcugu 16

408

›RNA

Homo sapiens

408

cugaauagcu gucaua 16

409

›RNA

Homo sapiens

409

uagcugucau aaaaug 16

410

›RNA

Homo sapiens

410

gucauaaaau gcuuuc 16

411

›RNA

Homo sapiens

411

aaagaaagau acucac 16

412

›RNA

Homo sapiens

412

auacucacau gaguuc 16

413

›RNA

Homo sapiens

413

augaguucuu gaagaa 16

414

›RNA

Homo sapiens

414

cuugaagaau agucau 16

415

›RNA

Homo sapiens

415

gaauagucau aacuag 16

416

›RNA

Homo sapiens

416

auuaagaucu guguuu 16

417

›RNA

Homo sapiens

417

uaagaucugu guuuua 16

418

›RNA

Homo sapiens

418

uuaguuuaau aguuug 16

419

›RNA

Homo sapiens

419

uuaauaguuu gaagug 16

420

›RNA

Homo sapiens

420

aguuugaagu gccugu 16

421

›RNA

Homo sapiens

421

ugaagugccu guuugg 16

422

›RNA

Homo sapiens

422

uguuugggau aaugau 16

423

›RNA

Homo sapiens

423

uugggauaau gauagg 16

424

›RNA

Homo sapiens

424

ggauaaugau agguaa 16

425

›RNA

Homo sapiens

425

uaauuuagau gaauuu 16

426

›RNA

Homo sapiens

426

aaaguuaucu gcaguu 16

427

›RNA

Homo sapiens

427

cugcaguuau guugag 16

428

›RNA

Homo sapiens

428

caguuauguu gagggc 16

429

›RNA

Homo sapiens

429

ggguuacagu guuuua 16

430

›RNA

Homo sapiens

430

uguuuuaucc gaaagu 16

431

›RNA

Homo sapiens

431

caauuccacu gucuug 16

432

›RNA

Homo sapiens

432

ccacugucuu guguuu 16

433

›RNA

Homo sapiens

433

acugucuugu guuuuc 16

434

›RNA

Homo sapiens

434

guguuuucau guugaa 16

435

›RNA

Homo sapiens

435

uuuucauguu gaaaau 16

436

›RNA

Homo sapiens

436

uguugaaaau acuuuu 16

437

›RNA

Homo sapiens

437

aaauacuuuu gcauuu 16

438

›RNA

Homo sapiens

438

uuuuuccuuu gagugc 16

439

›RNA

Homo sapiens

439

uccuuugagu gccaau 16

440

›RNA

Homo sapiens

440

auuucuuaau guaaca 16

441

›RNA

Homo sapiens

441

aauguaacau guuuac 16

442

›RNA

Homo sapiens

442

uaccuggccu gucuuu 16

443

›RNA

Homo sapiens

443

aacuauuuuu guauag 16

444

›RNA

Homo sapiens

444

auuuuuguau agugua 16

445

›RNA

Homo sapiens

445

uuuguauagu guaaac 16

446

›RNA

Homo sapiens

446

aguguaaacu gaaaca 16

447

›RNA

Homo sapiens

447

acugaaacau gcacau 16

448

›RNA

Homo sapiens

448

ugcacauuuu guacau 16

449

›RNA

Homo sapiens

449

uuuguacauu gugcuu 16

450

›RNA

Homo sapiens

450

uguacauugu gcuuuc 16

451

›RNA

Homo sapiens

451

gcuuucuuuu gugggu 16

452

›RNA

Homo sapiens

452

ugugggucau augcag 16

453

›RNA

Homo sapiens

453

ugggucauau gcagug 16

454

›RNA

Homo sapiens

454

cauaugcagu gugauc 16

455

›RNA

Homo sapiens

455

uaugcagugu gaucca 16

456

›RNA

Homo sapiens

456

ugauccaguu guuuuc 16

457

›RNA

Homo sapiens

457

ucauuugguu gcgcug 16

458

›RNA

Homo sapiens

458

auuugguugc gcugac 16

459

›RNA

Homo sapiens

459

ugguugcgcu gaccua 16

460

›RNA

Homo sapiens

460

accuaggaau guuggu 16

461

›RNA

Homo sapiens

461

uguuggucau aucaaa 16

462

›RNA

Homo sapiens

462

cauuaaaaau gaccac 16

463

›RNA

Homo sapiens

463

cucuuuuaau gaaauu 16

464

›RNA

Homo sapiens

464

acuuuuaaau guuuau 16

465

›RNA

Homo sapiens

465

aaauguuuau aggagu 16

466

›RNA

Homo sapiens

466

auaggaguau gugcug 16

467

›RNA

Homo sapiens

467

aggaguaugu gcugug 16

468

›RNA

Homo sapiens

468

aguaugugcu gugaag 16

469

›RNA

Homo sapiens

469

uaugugcugu gaagug 16

470

›RNA

Homo sapiens

470

gcugugaagu gaucua 16

471

›RNA

Homo sapiens

471

ucuaaaauuu guaaua 16

472

›RNA

Homo sapiens

472

aauuuguaau auuuuu 16

473

›RNA

Homo sapiens

473

uaauauuuuu gucaug 16

474

›RNA

Homo sapiens

474

uuuuugucau gaacug 16

475

›RNA

Homo sapiens

475

gucaugaacu guacua 16

476

›RNA

Homo sapiens

476

ccuaauuauu guaaug 16

477

›RNA

Homo sapiens

477

uuauuguaau guaaua 16

478

›RNA

Homo sapiens

478

guaauguaau aaaaau 16

479

›RNA

Homo sapiens

479

uaauaaaaau aguuac 16

480

›RNA

Homo sapiens

480

uaguuacagu gacuau 16

481

›RNA

Homo sapiens

481

cagugacuau gagugu 16

482

›RNA

Homo sapiens

482

gacuaugagu guguau 16

483

›RNA

Homo sapiens

483

cuaugagugu guauuu 16

484

›RNA

Homo sapiens

484

auuuauucau gcaaau 16

485

›RNA

Homo sapiens

485

augcaaauuu gaacug 16

486

›RNA

Homo sapiens

486

aauuugaacu guuugc 16

487

›RNA

Homo sapiens

487

ugaacuguuu gccccg 16

488

›RNA

Homo sapiens

488

uguuugcccc gaaaug 16

489

›RNA

Homo sapiens

489

gccccgaaau ggauau 16

490

›RNA

Homo sapiens

490

cgaaauggau auggau 16

491

›RNA

Homo sapiens

491

aaauggauau ggauac 16

492

›RNA

Homo sapiens

492

ggauauggau acuuua 16

493

›RNA

Homo sapiens

493

gauacuuuau aagcca 16

494

›RNA

Homo sapiens

494

uauaagccau agacac 16

495

›RNA

Homo sapiens

495

uagacacuau aguaua 16

496

›RNA

Homo sapiens

496

acuauaguau accagu 16

497

›RNA

Homo sapiens

497

guauaccagu gaaucu 16

498

›RNA

Homo sapiens

498

aaucuuuuau gcagcu 16

499

›RNA

Homo sapiens

499

uaugcagcuu guuaga 16

500

›RNA

Homo sapiens

500

ucuaaaaggu gcugug 16

501

›RNA

Homo sapiens

501

aaaaggugcu guggau 16

502

›RNA

Homo sapiens

502

ugcuguggau auuaug 16

503

›RNA

Homo sapiens

503

uggauauuau guaaag 16

504

›RNA

Homo sapiens

504

guaaaggcgu guuugc 16

505

›RNA

Homo sapiens

505

aggcguguuu gcuuaa 16

506

›RNA

Homo sapiens

506

aauuuuccau auuuag 16

507

›RNA

Homo sapiens

507

agaaguagau gcaaaa 16

508

›RNA

Homo sapiens

508

aaacaaaucu gccuuu 16

509

›RNA

Homo sapiens

509

cugccuuuau gacaaa 16

510

›RNA

Homo sapiens

510

acaaaaaaau aggaua 16

511

›RNA

Homo sapiens

511

aaaauaggau aacauu 16

512

›RNA

Homo sapiens

512

uuuuaucaau aaggua 16

513

›RNA

Homo sapiens

513

uaagguaauu gauaca 16

514

›RNA

Homo sapiens

514

gguaauugau acacaa 16

515

›RNA

Homo sapiens

515

cacaacaggu gacuug 16

516

›RNA

Homo sapiens

516

caacauuaau aaugga 16

517

›RNA

Homo sapiens

517

cauuaauaau ggaaau 16

518

›RNA

Homo sapiens

518

uaauggaaau aauuga 16

519

›RNA

Homo sapiens

519

ggaaauaauu gaauag 16

520

›RNA

Homo sapiens

520

auaauugaau aguuag 16

521

›RNA

Homo sapiens

521

aguuaguuau guaugu 16

522

›RNA

Homo sapiens

522

aguuauguau guuaau 16

523

›RNA

Homo sapiens

523

guauguuaau gccagu 16

524

›RNA

Homo sapiens

524

cagaaguaau gacucc 16

525

›RNA

Homo sapiens

525

augacuccau acauau 16

526

›RNA

Homo sapiens

526

cuccauacau auuauu 16

527

›RNA

Homo sapiens

527

uuauuucuau aacuac 16

528

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

528

cgccgugaug gcaugcacua ugcgcgggcc gccgcc 36

529

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

529

accuuugaug gcaugcacua ugcgcggccg ccgcca 36

530

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

530

aauggugaug gcaugcacua ugcgcggggg gccggg 36

531

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

531

gcgcuugaug gcaugcacua ugcgcggcuc ccaguc 36

532

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

532

cgccgugaug gcaugcacua ugcgcggcuc gcuccc 36

533

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

533

gccugugaug gcaugcacua ugcgcggccg cgcucg 36

534

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

534

gccuuugaug gcaugcacua ugcgcgagug ccugcg 36

535

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

535

ucccgugaug gcaugcacua ugcgcgaccu gggagc 36

536

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

536

uucagugaug gcaugcacua ugcgcgaggc cucucu 36

537

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

537

auuuuugaug gcaugcacua ugcgcgagca ggccuc 36

538

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

538

ucaguugaug gcaugcacua ugcgcgauuu ucagca 36

539

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

539

auauuugaug gcaugcacua ugcgcgaguc auuuuc 36

540

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

540

guuuaugaug gcaugcacua ugcgcgauuc agucau 36

541

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

541

aaguuugaug gcaugcacua ugcgcgauau ucaguc 36

542

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

542

uaccaugaug gcaugcacua ugcgcgaagu uuauau 36

543

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

543

cgccaugaug gcaugcacua ugcgcgaagc uccaac 36

544

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

544

caaggugaug gcaugcacua ugcgcgacuc uugccu 36

545

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

545

aucguugaug gcaugcacua ugcgcgaagg cacucu 36

546

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

546

uguauugaug gcaugcacua ugcgcgguca aggcac 36

547

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

547

agcugugaug gcaugcacua ugcgcgaucg ucaagg 36

548

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

548

guccaugaug gcaugcacua ugcgcgaaaa ugauuc 36

549

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

549

auauuugaug gcaugcacua ugcgcggucc acaaaa 36

550

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

550

gaucaugaug gcaugcacua ugcgcgauuc guccac 36

551

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

551

uggauugaug gcaugcacua ugcgcgauau ucgucc 36

552

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

552

uccucugaug gcaugcacua ugcgcgauug uuggau 36

553

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

553

uccauugaug gcaugcacua ugcgcgaauu acuacu 36

554

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

554

uucucugaug gcaugcacua ugcgcgauca auuacu 36

555

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

555

agagaugaug gcaugcacua ugcgcgaggu uucucc 36

556

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

556

gagaaugaug gcaugcacua ugcgcgaucc aagaga 36

557

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

557

uguguugaug gcaugcacua ugcgcggaga auaucc 36

558

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

558

cauugugaug gcaugcacua ugcgcgacug uacucc 36

559

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

559

ucccuugaug gcaugcacua ugcgcgauug cacugu 36

560

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

560

guccuugaug gcaugcacua ugcgcgaugu acuggu 36

561

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

561

auacaugaug gcaugcacua ugcgcgaaag aaagcc 36

562

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

562

aaauaugaug gcaugcacua ugcgcgacaa agaaag 36

563

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

563

uauggugaug gcaugcacua ugcgcgaaau acacaa 36

564

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

564

uuauuugaug gcaugcacua ugcgcgaugg caaaua 36

565

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

565

aguauugaug gcaugcacua ugcgcgauuu auggca 36

566

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

566

uuuagugaug gcaugcacua ugcgcgauua uuuaug 36

567

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

567

aucuuugaug gcaugcacua ugcgcgaaau gauuua 36

568

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

568

gugaaugaug gcaugcacua ugcgcgaucu ucaaau 36

569

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

569

uucucugaug gcaugcacua ugcgcgauaa ugguga 36

570

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

570

aucuuugaug gcaugcacua ugcgcgagag uccuua 36

571

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

571

agguaugaug gcaugcacua ugcgcgaucu ucagag 36

572

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

572

aggacugaug gcaugcacua ugcgcgauag guacau 36

573

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

573

acauuugaug gcaugcacua ugcgcgauuu ccuacu 36

574

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

574

aaucaugaug gcaugcacua ugcgcgauuu auuucc 36

575

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

575

caaauugaug gcaugcacua ugcgcgacau uuauuu 36

576

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

576

gaaggugaug gcaugcacua ugcgcgaaau cacauu 36

577

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

577

aauucugaug gcaugcacua ugcgcgauaa cuucuu 36

578

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

578

uguuuugaug gcaugcacua ugcgcgaaua aaagga 36

579

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

579

aucaaugaug gcaugcacua ugcgcgaccc ugucuu 36

580

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

580

aucauugaug gcaugcacua ugcgcgaaca cccugu 36

581

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

581

ggcauugaug gcaugcacua ugcgcgauca acaccc 36

582

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

582

gaaggugaug gcaugcacua ugcgcgauca ucaaca 36

583

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

583

uaaugugaug gcaugcacua ugcgcgauag aaggca 36

584

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

584

uuucuugaug gcaugcacua ugcgcggaac uaaugu 36

585

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

585

guuuuugaug gcaugcacua ugcgcggaau uucucg 36

586

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

586

uucuuugaug gcaugcacua ugcgcgaugu uuucga 36

587

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

587

uugcuugaug gcaugcacua ugcgcgaucu uuucuu 36

588

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

588

uuuacugaug gcaugcacua ugcgcgaucu uugcuc 36

589

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

589

uuacaugaug gcaugcacua ugcgcgacuu ugucuu 36

590

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

590

aauuaugaug gcaugcacua ugcgcgacac uuuguc 36

591

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

591

auuuaugaug gcaugcacua ugcgcgauaa uuacac 36

592

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

592

aauugugaug gcaugcacua ugcgcgauuu acauaa 36

593

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

593

aaguaugaug gcaugcacua ugcgcgaaau uguauu 36

594

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

594

acuagugaug gcaugcacua ugcgcgaugc cuuaag 36

595

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

595

auguaugaug gcaugcacua ugcgcgaaaa auuacc 36

596

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

596

uaaaaugaug gcaugcacua ugcgcgaaau gcuaau 36

597

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

597

uggagugaug gcaugcacua ugcgcgagga aaaaaa 36

598

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

598

gucugugaug gcaugcacua ugcgcgaugg agcagg 36

599

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

599

gcuaaugaug gcaugcacua ugcgcgaguc ugcaug 36

600

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

600

auaagugaug gcaugcacua ugcgcgauuu aaggua 36

601

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

601

acuguugaug gcaugcacua ugcgcgauuu uaaaau 36

602

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

602

cacuuugaug gcaugcacua ugcgcggagg aaaaaa 36

603

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

603

acuggugaug gcaugcacua ugcgcgacuu cgagga 36

604

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

604

uaguuugaug gcaugcacua ugcgcgaaaa accaaa 36

605

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

605

acaggugaug gcaugcacua ugcgcgauug cuaguu 36

606

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

606

uuucaugaug gcaugcacua ugcgcgaggc auugcu 36

607

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

607

uuuuuugaug gcaugcacua ugcgcgacag gcauug 36

608

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

608

guauuugaug gcaugcacua ugcgcgaguu ucuuuu 36

609

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

609

uuaggugaug gcaugcacua ugcgcgauuc aguuuc 36

610

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

610

caagaugaug gcaugcacua ugcgcgagaa aucuua 36

611

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

611

gcaugugaug gcaugcacua ugcgcgacca aaaacc 36

612

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

612

aacugugaug gcaugcacua ugcgcgaugc accaaa 36

613

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

613

guaauugaug gcaugcacua ugcgcgaacu gcaugc 36

614

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

614

auucaugaug gcaugcacua ugcgcgacuu gguaag 36

615

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

615

acauuugaug gcaugcacua ugcgcgacac uuggua 36

616

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

616

accaaugaug gcaugcacua ugcgcgauuc acacuu 36

617

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

617

uuucaugaug gcaugcacua ugcgcgacca acauuc 36

618

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

618

uguuuugaug gcaugcacua ugcgcgacac caacau 36

619

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

619

agcuuugaug gcaugcacua ugcgcgauua auuugu 36

620

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

620

ugauuugaug gcaugcacua ugcgcgaaaa gcuuca 36

621

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

621

aaacaugaug gcaugcacua ugcgcgagaa uaggga 36

622

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

622

uaaaaugaug gcaugcacua ugcgcgacag aauagg 36

623

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

623

ccauuugaug gcaugcacua ugcgcgaugu gacuag 36

624

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

624

uaaucugaug gcaugcacua ugcgcgauuu auguga 36

625

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

625

ggucuugaug gcaugcacua ugcgcgaacu gaaauu 36

626

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

626

uguuuugaug gcaugcacua ugcgcgagua aaaacc 36

627

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

627

ucccuugaug gcaugcacua ugcgcgaaug uuucag 36

628

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

628

aagccugaug gcaugcacua ugcgcgauaa auuugu 36

629

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

629

aucauugaug gcaugcacua ugcgcgagga agccca 36

630

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

630

aucauugaug gcaugcacua ugcgcgauca ggaagc 36

631

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

631

agaauugaug gcaugcacua ugcgcgauca ucagga 36

632

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

632

uaggaugaug gcaugcacua ugcgcgauga ugccua 36

633

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

633

caaacugaug gcaugcacua ugcgcgauag gacaug 36

634

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

634

gaugaugaug gcaugcacua ugcgcgaaac uauagg 36

635

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

635

uucauugaug gcaugcacua ugcgcgaggg augaca 36

636

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

636

acauuugaug gcaugcacua ugcgcgauca gggaug 36

637

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

637

cuuuaugaug gcaugcacua ugcgcgauuc aucagg 36

638

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

638

gugaaugaug gcaugcacua ugcgcgagug uaacuu 36

639

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

639

ggagaugaug gcaugcacua ugcgcgaaaa ccuuug 36

640

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

640

aauagugaug gcaugcacua ugcgcgagug gaaagg 36

641

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

641

gugacugaug gcaugcacua ugcgcgauga cuaaua 36

642

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

642

uauaaugaug gcaugcacua ugcgcgauuu ugggga 36

643

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

643

aaaaaugaug gcaugcacua ugcgcgauaa uauuuu 36

644

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

644

cuuuuugaug gcaugcacua ugcgcgauag aaaaaa 36

645

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

645

uuuucugaug gcaugcacua ugcgcgauuu uuuucu 36

646

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

646

guuucugaug gcaugcacua ugcgcgauug ccuugu 36

647

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

647

ggccuugaug gcaugcacua ugcgcgauaa uaguuu 36

648

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

648

uaauuugaug gcaugcacua ugcgcgaucu aaugug 36

649

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

649

gucuuugaug gcaugcacua ugcgcgauag uaauuu 36

650

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

650

aaagcugaug gcaugcacua ugcgcgauua ggaguc 36

651

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

651

cuuaaugaug gcaugcacua ugcgcgagga aaaagc 36

652

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

652

ccauuugaug gcaugcacua ugcgcgauac uggguc 36

653

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

653

aauccugaug gcaugcacua ugcgcgauuc auacug 36

654

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

654

guugcugaug gcaugcacua ugcgcgauaa uaaucc 36

655

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

655

guaaaugaug gcaugcacua ugcgcgauag ccccaa 36

656

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

656

aguagugaug gcaugcacua ugcgcgaugu aaauau 36

657

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

657

auuauugaug gcaugcacua ugcgcgauaa aaauuu 36

658

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

658

ucaauugaug gcaugcacua ugcgcgauua uaaaaa 36

659

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

659

cuuuuugaug gcaugcacua ugcgcgaauu auuaua 36

660

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

660

uuuuuugaug gcaugcacua ugcgcgauac uuguua 36

661

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

661

auuccugaug gcaugcacua ugcgcgauga gaauuu 36

662

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

662

gacuaugaug gcaugcacua ugcgcgauuu aauucc 36

663

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

663

ugacaugaug gcaugcacua ugcgcgaggg agacua 36

664

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

664

ucugaugaug gcaugcacua ugcgcgacag ggagac 36

665

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

665

aagagugaug gcaugcacua ugcgcgaguc ugacac 36

666

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

666

uauacugaug gcaugcacua ugcgcgauga aagagc 36

667

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

667

aaaguugaug gcaugcacua ugcgcgauac uaugaa 36

668

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

668

agacuugaug gcaugcacua ugcgcgaagu ugaaga 36

669

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

669

aucuuugaug gcaugcacua ugcgcgaaag acucaa 36

670

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

670

aaaacugaug gcaugcacua ugcgcgaucu ucaaag 36

671

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

671

acaagugaug gcaugcacua ugcgcgagaa uuaaaa 36

672

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

672

ugucaugaug gcaugcacua ugcgcgaagc agaauu 36

673

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

673

aauguugaug gcaugcacua ugcgcgacaa gcagaa 36

674

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

674

uaagcugaug gcaugcacua ugcgcgauaa cuggcc 36

675

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

675

uucaaugaug gcaugcacua ugcgcgaccu aauaag 36

676

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

676

cucuuugaug gcaugcacua ugcgcgaaca ccuaau 36

677

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

677

gcuugugaug gcaugcacua ugcgcgaacc uugguc 36

678

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

678

ucacaugaug gcaugcacua ugcgcgaggg ccuggc 36

679

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

679

guucaugaug gcaugcacua ugcgcgacag ggccug 36

680

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

680

agguuugaug gcaugcacua ugcgcgacac agggcc 36

681

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

681

aagcuugaug gcaugcacua ugcgcgaagg uucaca 36

682

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

682

cucucugaug gcaugcacua ugcgcgauga aagcuc 36

683

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

683

cagucugaug gcaugcacua ugcgcgaugc ugugaa 36

684

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

684

gcacaugaug gcaugcacua ugcgcgaguc caugcu 36

685

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

685

gggcaugaug gcaugcacua ugcgcgacag uccaug 36

686

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

686

uggggugaug gcaugcacua ugcgcgacac agucca 36

687

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

687

ccacuugaug gcaugcacua ugcgcgggau gaccgu 36

688

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

688

ucguaugaug gcaugcacua ugcgcgaacc acucgg 36

689

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

689

ugcauugaug gcaugcacua ugcgcgguac aaccac 36

690

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

690

caaugugaug gcaugcacua ugcgcgaucg uacaac 36

691

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

691

cucccugaug gcaugcacua ugcgcgauuu uugacu 36

692

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

692

ugagcugaug gcaugcacua ugcgcgaucc aaacug 36

693

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

693

gauugugaug gcaugcacua ugcgcgaucu uguuga 36

694

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

694

caccaugaug gcaugcacua ugcgcgagag ugagau 36

695

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

695

gucagugaug gcaugcacua ugcgcgagga ccacca 36

696

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

696

uuuguugaug gcaugcacua ugcgcgagca ggacca 36

697

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

697

aaaagugaug gcaugcacua ugcgcgaaug cucuug 36

698

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

698

agaaaugaug gcaugcacua ugcgcgaaaa gcaaug 36

699

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

699

guuaaugaug gcaugcacua ugcgcgauuu aaaagu 36

700

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

700

aaucuugaug gcaugcacua ugcgcgaacu uuugag 36

701

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

701

uggcaugaug gcaugcacua ugcgcgacca ccaccc 36

702

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

702

cuuggugaug gcaugcacua ugcgcgacac caccac 36

703

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

703

cacuuugaug gcaugcacua ugcgcgauug uuuaaa 36

704

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

704

uuuuuugaug gcaugcacua ugcgcgacuu cauugu 36

705

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

705

uuaugugaug gcaugcacua ugcgcgaaug uuaauu 36

706

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

706

guguuugaug gcaugcacua ugcgcgaugc aauguu 36

707

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

707

uggauugaug gcaugcacua ugcgcgagac uugaaa 36

708

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

708

uuaaaugaug gcaugcacua ugcgcgaugg aucaga 36

709

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

709

agcauugaug gcaugcacua ugcgcgauua aauaug 36

710

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

710

uaaagugaug gcaugcacua ugcgcgauua uuaaau 36

711

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

711

auuuuugaug gcaugcacua ugcgcgauuu uaaagc 36

712

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

712

guuuuugaug gcaugcacua ugcgcgauuu uuauuu 36

713

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

713

uuuauugaug gcaugcacua ugcgcgaaaa ggauug 36

714

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

714

aaauuugaug gcaugcacua ugcgcgauca aaagga 36

715

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

715

aguaaugaug gcaugcacua ugcgcgauuu uaaauu 36

716

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

716

ucauuugaug gcaugcacua ugcgcgauuu uaaaau 36

717

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

717

cacuuugaug gcaugcacua ugcgcgauuu auuuua 36

718

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

718

caucuugaug gcaugcacua ugcgcgacuu cauuua 36

719

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

719

caugcugaug gcaugcacua ugcgcgaucu cacuuc 36

720

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

720

cucacugaug gcaugcacua ugcgcgaugc caucuc 36

721

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

721

caccuugaug gcaugcacua ugcgcgacca ugccau 36

722

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

722

acuuuugaug gcaugcacua ugcgcgaccu caccau 36

723

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

723

accaaugaug gcaugcacua ugcgcgaacc uagucc 36

724

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

724

uaaguugaug gcaugcacua ugcgcgacca acaacc 36

725

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

725

acaccugaug gcaugcacua ugcgcgaucu agaacc 36

726

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

726

aaagaugaug gcaugcacua ugcgcgaccu aucuag 36

727

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

727

aaaauugaug gcaugcacua ugcgcgagag uccuaa 36

728

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

728

guccuugaug gcaugcacua ugcgcgaaaa ucagag 36

729

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

729

uuuaaugaug gcaugcacua ugcgcgauga agaaau 36

730

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

730

aaucaugaug gcaugcacua ugcgcgauag uguaaa 36

731

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

731

uaaauugaug gcaugcacua ugcgcgacau agugua 36

732

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

732

uggaaugaug gcaugcacua ugcgcgauaa aucaca 36

733

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

733

auccuugaug gcaugcacua ugcgcgaugu aaaugg 36

734

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

734

aagugugaug gcaugcacua ugcgcgaucc uuaugu 36

735

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

735

cuugaugaug gcaugcacua ugcgcgaaau aagugu 36

736

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

736

auuuaugaug gcaugcacua ugcgcgagau ugugcu 36

737

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

737

uguaaugaug gcaugcacua ugcgcgauag guuaaa 36

738

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

738

acuggugaug gcaugcacua ugcgcgacug aagaug 36

739

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

739

uugcaugaug gcaugcacua ugcgcgaauu uugccc 36

740

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

740

ucuugugaug gcaugcacua ugcgcgacaa uuuugc 36

741

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

741

aacuuugaug gcaugcacua ugcgcgaccu cuugca 36

742

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

742

ucaaaugaug gcaugcacua ugcgcgauaa acuuca 36

743

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

743

auauuugaug gcaugcacua ugcgcgaaau auaaac 36

744

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

744

auggaugaug gcaugcacua ugcgcgauuc aaauau 36

745

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

745

acuaaugaug gcaugcacua ugcgcgaugg aagaag 36

746

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

746

gaugaugaug gcaugcacua ugcgcgacua auaugg 36

747

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

747

ggaggugaug gcaugcacua ugcgcgaaga ugacac 36

748

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

748

uggggugaug gcaugcacua ugcgcgaugu ggaagg 36

749

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

749

caaguugaug gcaugcacua ugcgcgaugg ggcaug 36

750

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

750

ugcauugaug gcaugcacua ugcgcgaagu cauggg 36

751

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

751

aacugugaug gcaugcacua ugcgcgauca agucau 36

752

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

752

acaagugaug gcaugcacua ugcgcgauua aaacug 36

753

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

753

aauuaugaug gcaugcacua ugcgcgaagu auuaaa 36

754

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

754

aaucuugaug gcaugcacua ugcgcgaugg uuaggg 36

755

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

755

agcagugaug gcaugcacua ugcgcgagua aaucuu 36

756

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

756

cacagugaug gcaugcacua ugcgcgagca guaaau 36

757

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

757

auccaugaug gcaugcacua ugcgcgagca gcagua 36

758

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

758

ggagaugaug gcaugcacua ugcgcgaucc acagca 36

759

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

759

aacuuugaug gcaugcacua ugcgcgaugg agauau 36

760

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

760

ugacuugaug gcaugcacua ugcgcgagug ggaaaa 36

761

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

761

uagggugaug gcaugcacua ugcgcgauuu cugaug 36

762

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

762

ucuguugaug gcaugcacua ugcgcgagau ucucuu 36

763

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

763

uauggugaug gcaugcacua ugcgcgaucu gucaga 36

764

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

764

cccuuugaug gcaugcacua ugcgcgaugg uaucug 36

765

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

765

uagguugaug gcaugcacua ugcgcgaaau cccuuu 36

766

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

766

agcauugaug gcaugcacua ugcgcgagcc accacc 36

767

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

767

caaagugaug gcaugcacua ugcgcgauca gccacc 36

768

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

768

auguuugaug gcaugcacua ugcgcgaaag caucag 36

769

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

769

ggcagugaug gcaugcacua ugcgcgaaag agaugu 36

770

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

770

uugggugaug gcaugcacua ugcgcgagca aagaga 36

771

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

771

acuguugaug gcaugcacua ugcgcggcua auggau 36

772

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

772

cuauuugaug gcaugcacua ugcgcgauac cagggu 36

773

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

773

cugucugaug gcaugcacua ugcgcgauuc auacca 36

774

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

774

aucuuugaug gcaugcacua ugcgcgauua aauucu 36

775

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

775

ugcacugaug gcaugcacua ugcgcgaucu uuauua 36

776

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

776

uucugugaug gcaugcacua ugcgcgacua ucuuua 36

777

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

777

cuaguugaug gcaugcacua ugcgcgauag auuacc 36

778

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

778

gaaugugaug gcaugcacua ugcgcgauua cuguua 36

779

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

779

uaaaaugaug gcaugcacua ugcgcgaaug gaaugu 36

780

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

780

cauugugaug gcaugcacua ugcgcgauga agauuu 36

781

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

781

uuuuuugaug gcaugcacua ugcgcgauug caugaa 36

782

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

782

uaaagugaug gcaugcacua ugcgcgauuu uucauu 36

783

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

783

agcuuugaug gcaugcacua ugcgcgauga auuaaa 36

784

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

784

ucugaugaug gcaugcacua ugcgcgacca aaaaaa 36

785

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

785

aagagugaug gcaugcacua ugcgcggaga cucuga 36

786

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

786

ggugaugaug gcaugcacua ugcgcgaaga gcgaga 36

787

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

787

cacugugaug gcaugcacua ugcgcgauuc cagccu 36

788

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

788

gauggugaug gcaugcacua ugcgcggcca cugcau 36

789

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

789

gguugugaug gcaugcacua ugcgcgagug agcuga 36

790

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

790

agaauugaug gcaugcacua ugcgcggcuu gaaccu 36

791

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

791

cgaggugaug gcaugcacua ugcgcgacga gaaucg 36

792

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

792

cuacuugaug gcaugcacua ugcgcgagga ggccga 36

793

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

793

gugcaugaug gcaugcacua ugcgcgacgc cuguaa 36

794

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

794

uagugugaug gcaugcacua ugcgcgacac gccugu 36

795

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

795

aaauaugaug gcaugcacua ugcgcgaaaa auuagu 36

796

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

796

gccaaugaug gcaugcacua ugcgcgaggu gaaacc 36

797

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

797

gaguuugaug gcaugcacua ugcgcggaga ccagcc 36

798

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

798

gagguugaug gcaugcacua ugcgcgagga guucga 36

799

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

799

ugaauugaug gcaugcacua ugcgcgacuu gagguc 36

800

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

800

agguuugaug gcaugcacua ugcgcgauga ggccaa 36

801

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

801

caaaaugaug gcaugcacua ugcgcgaggu uuauga 36

802

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

802

uucugugaug gcaugcacua ugcgcgaaaa cagguu 36

803

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

803

auaaaugaug gcaugcacua ugcgcgauuu gcugaa 36

804

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

804

gcacuugaug gcaugcacua ugcgcgaaua aauauu 36

805

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

805

guaggugaug gcaugcacua ugcgcgacuc aauaaa 36

806

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

806

acuggugaug gcaugcacua ugcgcgaucu gguagg 36

807

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

807

uugugugaug gcaugcacua ugcgcgggug acuggc 36

808

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

808

uaccaugaug gcaugcacua ugcgcgauac ccagug 36

809

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

809

gauacugaug gcaugcacua ugcgcgauau acccag 36

810

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

810

gggauugaug gcaugcacua ugcgcgaugu cucuug 36

811

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

811

acuagugaug gcaugcacua ugcgcgagua ccuaag 36

812

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

812

gaccaugaug gcaugcacua ugcgcgacua gcagua 36

813

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

813

uauuaugaug gcaugcacua ugcgcgagac cacacu 36

814

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

814

uaagaugaug gcaugcacua ugcgcgauua cagacc 36

815

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

815

ggucgugaug gcaugcacua ugcgcgauac caaagg 36

816

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

816

uggguugaug gcaugcacua ugcgcgguau accaaa 36

817

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

817

cguguugaug gcaugcacua ugcgcgaucu cugggu 36

818

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

818

cgcauugaug gcaugcacua ugcgcggugu uaucuc 36

819

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

819

auacgugaug gcaugcacua ugcgcgaucg uguuau 36

820

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

820

cuuugugaug gcaugcacua ugcgcgaaaa cuaaaa 36

821

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

821

uggcaugaug gcaugcacua ugcgcgagag accaaa 36

822

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

822

gcuggugaug gcaugcacua ugcgcgacag agacca 36

823

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

823

acaauugaug gcaugcacua ugcgcgauag agcugg 36

824

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

824

caaaaugaug gcaugcacua ugcgcgaauu auagag 36

825

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

825

cguagugaug gcaugcacua ugcgcgaaaa caauua 36

826

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

826

ggaauugaug gcaugcacua ugcgcgguag caaaac 36

827

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

827

aguuuugaug gcaugcacua ugcgcgagug gaaucg 36

828

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

828

uugauugaug gcaugcacua ugcgcggaag aguuuc 36

829

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

829

auuuaugaug gcaugcacua ugcgcgauaa aguagc 36

830

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

830

uaaaaugaug gcaugcacua ugcgcgaaug aaguga 36

831

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

831

aaguuugaug gcaugcacua ugcgcgauuc cuuuaa 36

832

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

832

auaauugaug gcaugcacua ugcgcgaagu uuauuc 36

833

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

833

aacaaugaug gcaugcacua ugcgcgauaa ucaagu 36

834

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

834

aaaaaugaug gcaugcacua ugcgcgaaua uaauca 36

835

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

835

acaguugaug gcaugcacua ugcgcgaugc caaaua 36

836

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

836

aaucaugaug gcaugcacua ugcgcgaguu augcca 36

837

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

837

agaauugaug gcaugcacua ugcgcgacag uuaugc 36

838

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

838

guguaugaug gcaugcacua ugcgcgagua auuguc 36

839

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

839

acauaugaug gcaugcacua ugcgcgaccu uaaugu 36

840

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

840

ucugaugaug gcaugcacua ugcgcgauac accuua 36

841

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

841

augaaugaug gcaugcacua ugcgcgaucu gacaua 36

842

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

842

gucaaugaug gcaugcacua ugcgcgauga auaucu 36

843

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

843

uggguugaug gcaugcacua ugcgcgaaua ugaaua 36

844

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

844

uuacaugaug gcaugcacua ugcgcgauuu ggguca 36

845

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

845

uauuaugaug gcaugcacua ugcgcgacau uugggu 36

846

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

846

uggaaugaug gcaugcacua ugcgcgauua cacauu 36

847

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

847

uuaugugaug gcaugcacua ugcgcgagag aaaacu 36

848

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

848

uuacuugaug gcaugcacua ugcgcgaugc agagaa 36

849

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

849

aaguaugaug gcaugcacua ugcgcgauuu uaauua 36

850

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

850

uuaagugaug gcaugcacua ugcgcgauau uuuaau 36

851

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

851

aaaacugaug gcaugcacua ugcgcgauua auuuuu 36

852

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

852

cuguuugaug gcaugcacua ugcgcgauuu guaccc 36

853

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

853

ucaggugaug gcaugcacua ugcgcgacug uuuauu 36

854

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

854

uaguuugaug gcaugcacua ugcgcgaggc acuguu 36

855

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

855

uuuuaugaug gcaugcacua ugcgcgauag aaguuu 36

856

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

856

gaaauugaug gcaugcacua ugcgcgauag ugauuu 36

857

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

857

caauuugaug gcaugcacua ugcgcgagaa aucaua 36

858

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

858

cauagugaug gcaugcacua ugcgcgaauu cagaaa 36

859

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

859

uuucaugaug gcaugcacua ugcgcgauag caauuc 36

860

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

860

aguuuugaug gcaugcacua ugcgcgacau agcaau 36

861

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

861

cuaaaugaug gcaugcacua ugcgcgagug uuccaa 36

862

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

862

cuuaaugaug gcaugcacua ugcgcgaccc uaccua 36

863

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

863

uguguugaug gcaugcacua ugcgcgaagu cuuaac 36

864

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

864

auggcugaug gcaugcacua ugcgcgauuu cuuucu 36

865

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

865

ugaagugaug gcaugcacua ugcgcgaugg ccauuu 36

866

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

866

cacugugaug gcaugcacua ugcgcgaguu ccugaa 36

867

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

867

auaagugaug gcaugcacua ugcgcgacug caguuc 36

868

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

868

ccccuugaug gcaugcacua ugcgcgauaa gcacug 36

869

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

869

cuaaaugaug gcaugcacua ugcgcgaucc ccucau 36

870

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

870

aaauuugaug gcaugcacua ugcgcgaaga ggccua 36

871

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

871

uacauugaug gcaugcacua ugcgcgaaaa auucaa 36

872

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

872

aucuaugaug gcaugcacua ugcgcgauca aaaauu 36

873

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

873

augccugaug gcaugcacua ugcgcgaucu acauca 36

874

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

874

guucaugaug gcaugcacua ugcgcgauaa agguaa 36

875

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

875

aaguuugaug gcaugcacua ugcgcgacau aaaggu 36

876

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

876

ccauuugaug gcaugcacua ugcgcgaaag uucaca 36

877

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

877

uaaacugaug gcaugcacua ugcgcgauuc aaaguu 36

878

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

878

aaaaaugaug gcaugcacua ugcgcgaaau cuuuug 36

879

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

879

cucuaugaug gcaugcacua ugcgcgaaaa acaaau 36

880

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

880

acauuugaug gcaugcacua ugcgcgauuu cuagaa 36

881

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

881

gguaaugaug gcaugcacua ugcgcgauuu auuucu 36

882

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

882

uucaaugaug gcaugcacua ugcgcgaagg auuuuu 36

883

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

883

aacuuugaug gcaugcacua ugcgcgaaca aggauu 36

884

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

884

aagucugaug gcaugcacua ugcgcgaugu aauuua 36

885

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

885

acaaaugaug gcaugcacua ugcgcgaugu uaaugc 36

886

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

886

uuccaugaug gcaugcacua ugcgcgaaac auguua 36

887

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

887

ugcuaugaug gcaugcacua ugcgcgauuc uuccac 36

888

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

888

ucugcugaug gcaugcacua ugcgcgauau ucuucc 36

889

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

889

uacaaugaug gcaugcacua ugcgcgauac gucugc 36

890

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

890

ugauaugaug gcaugcacua ugcgcgaaua uacguc 36

891

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

891

ucacuugaug gcaugcacua ugcgcgaaau gauaca 36

892

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

892

acauuugaug gcaugcacua ugcgcgacuc aaauga 36

893

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

893

gggaaugaug gcaugcacua ugcgcgauuc acucaa 36

894

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

894

ugacuugaug gcaugcacua ugcgcgaguu aaauag 36

895

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

895

cuaugugaug gcaugcacua ugcgcgagug ugacuc 36

896

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

896

auuccugaug gcaugcacua ugcgcgaugc agugug 36

897

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

897

uaaccugaug gcaugcacua ugcgcgauaa aaguua 36

898

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

898

gacaaugaug gcaugcacua ugcgcgaguu uugaua 36

899

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

899

ggugaugaug gcaugcacua ugcgcgaaca guuuug 36

900

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

900

uugugugaug gcaugcacua ugcgcgaaug gugaca 36

901

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

901

uaggaugaug gcaugcacua ugcgcgaaaa uugugc 36

902

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

902

guauaugaug gcaugcacua ugcgcgauua ggacaa 36

903

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

903

auguaugaug gcaugcacua ugcgcgauau uaggac 36

904

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

904

cuaugugaug gcaugcacua ugcgcgauau auuagg 36

905

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

905

guuucugaug gcaugcacua ugcgcgaugu auauau 36

906

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

906

ccccaugaug gcaugcacua ugcgcgaaag uuucua 36

907

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

907

cuuaaugaug gcaugcacua ugcgcgaugc cccaca 36

908

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

908

uugugugaug gcaugcacua ugcgcgaaac uguaac 36

909

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

909

gaauaugaug gcaugcacua ugcgcgaaau gagaug 36

910

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

910

aaaauugaug gcaugcacua ugcgcgaaug gaauac 36

911

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

911

uuauaugaug gcaugcacua ugcgcgauac uguuuu 36

912

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

912

aguuaugaug gcaugcacua ugcgcgauau acuguu 36

913

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

913

aaaguugaug gcaugcacua ugcgcgauau auacug 36

914

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

914

aucuuugaug gcaugcacua ugcgcgagau aguuuu 36

915

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

915

uuugaugaug gcaugcacua ugcgcgaaau ggaaau 36

916

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

916

gaaauugaug gcaugcacua ugcgcgauua cuuuuu 36

917

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

917

auuauugaug gcaugcacua ugcgcgaaga aaucau 36

918

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

918

acaauugaug gcaugcacua ugcgcgauca agaaau 36

919

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

919

cuacaugaug gcaugcacua ugcgcgaauu aucaag 36

920

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

920

cacuaugaug gcaugcacua ugcgcgacaa uuauca 36

921

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

921

acauuugaug gcaugcacua ugcgcgacua cacaau 36

922

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

922

aaaaaugaug gcaugcacua ugcgcgauuc acuaca 36

923

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

923

gcuuuugaug gcaugcacua ugcgcgaagg uaacug 36

924

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

924

aaauuugaug gcaugcacua ugcgcgagcu uucaag 36

925

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

925

cuaaaugaug gcaugcacua ugcgcgauaa auucag 36

926

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

926

uaacaugaug gcaugcacua ugcgcgagaa guuacu 36

927

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

927

auuaaugaug gcaugcacua ugcgcgacag aaguua 36

928

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

928

uccagugaug gcaugcacua ugcgcgauua acacag 36

929

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

929

caugcugaug gcaugcacua ugcgcgaucc aguauu 36

930

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

930

gaauuugaug gcaugcacua ugcgcgaugc uaucca 36

931

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

931

caaugugaug gcaugcacua ugcgcgagaa uucaug 36

932

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

932

uuucuugaug gcaugcacua ugcgcgaaug cagaau 36

933

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

933

cuauuugaug gcaugcacua ugcgcgaguu ucucaa 36

934

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

934

acagcugaug gcaugcacua ugcgcgauuc aguuuc 36

935

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

935

uaugaugaug gcaugcacua ugcgcgagcu auucag 36

936

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

936

cauuuugaug gcaugcacua ugcgcgauga cagcua 36

937

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

937

gaaagugaug gcaugcacua ugcgcgauuu uaugac 36

938

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

938

gugagugaug gcaugcacua ugcgcgaucu uucuuu 36

939

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

939

gaacuugaug gcaugcacua ugcgcgaugu gaguau 36

940

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

940

uucuuugaug gcaugcacua ugcgcgaaga acucau 36

941

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

941

augacugaug gcaugcacua ugcgcgauuc uucaag 36

942

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

942

cuaguugaug gcaugcacua ugcgcgauga cuauuc 36

943

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

943

aaacaugaug gcaugcacua ugcgcgagau cuuaau 36

944

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

944

uaaaaugaug gcaugcacua ugcgcgacag aucuua 36

945

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

945

caaacugaug gcaugcacua ugcgcgauua aacuaa 36

946

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

946

cacuuugaug gcaugcacua ugcgcgaaac uauuaa 36

947

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

947

acaggugaug gcaugcacua ugcgcgacuu caaacu 36

948

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

948

ccaaaugaug gcaugcacua ugcgcgaggc acuuca 36

949

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

949

aucauugaug gcaugcacua ugcgcgaucc caaaca 36

950

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

950

ccuauugaug gcaugcacua ugcgcgauua ucccaa 36

951

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

951

uuaccugaug gcaugcacua ugcgcgauca uuaucc 36

952

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

952

aaauuugaug gcaugcacua ugcgcgaucu aaauua 36

953

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

953

aacugugaug gcaugcacua ugcgcgagau aacuuu 36

954

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

954

cucaaugaug gcaugcacua ugcgcgauaa cugcag 36

955

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

955

gcccuugaug gcaugcacua ugcgcgaaca uaacug 36

956

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

956

uaaaaugaug gcaugcacua ugcgcgacug uaaccc 36

957

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

957

acuuuugaug gcaugcacua ugcgcgggau aaaaca 36

958

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

958

caagaugaug gcaugcacua ugcgcgagug gaauug 36

959

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

959

aaacaugaug gcaugcacua ugcgcgaaga cagugg 36

960

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

960

gaaaaugaug gcaugcacua ugcgcgacaa gacagu 36

961

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

961

uucaaugaug gcaugcacua ugcgcgauga aaacac 36

962

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

962

auuuuugaug gcaugcacua ugcgcgaaca ugaaaa 36

963

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

963

aaaagugaug gcaugcacua ugcgcgauuu ucaaca 36

964

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

964

aaaugugaug gcaugcacua ugcgcgaaaa guauuu 36

965

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

965

gcacuugaug gcaugcacua ugcgcgaaag gaaaaa 36

966

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

966

auuggugaug gcaugcacua ugcgcgacuc aaagga 36

967

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

967

uguuaugaug gcaugcacua ugcgcgauua agaaau 36

968

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

968

guaaaugaug gcaugcacua ugcgcgaugu uacauu 36

969

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

969

aaagaugaug gcaugcacua ugcgcgaggc caggua 36

970

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

970

cuauaugaug gcaugcacua ugcgcgaaaa auaguu 36

971

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

971

uacacugaug gcaugcacua ugcgcgauac aaaaau 36

972

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

972

guuuaugaug gcaugcacua ugcgcgacua uacaaa 36

973

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

973

uguuuugaug gcaugcacua ugcgcgaguu uacacu 36

974

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

974

augugugaug gcaugcacua ugcgcgaugu uucagu 36

975

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

975

auguaugaug gcaugcacua ugcgcgaaaa ugugca 36

976

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

976

aagcaugaug gcaugcacua ugcgcgaaug uacaaa 36

977

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

977

gaaagugaug gcaugcacua ugcgcgacaa uguaca 36

978

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

978

acccaugaug gcaugcacua ugcgcgaaaa gaaagc 36

979

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

979

cugcaugaug gcaugcacua ugcgcgauga cccaca 36

980

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

980

cacugugaug gcaugcacua ugcgcgauau gaccca 36

981

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

981

gaucaugaug gcaugcacua ugcgcgacug cauaug 36

982

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

982

uggauugaug gcaugcacua ugcgcgacac ugcaua 36

983

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

983

gaaaaugaug gcaugcacua ugcgcgaacu ggauca 36

984

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

984

cagcgugaug gcaugcacua ugcgcgaacc aaauga 36

985

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

985

gucagugaug gcaugcacua ugcgcggcaa ccaaau 36

986

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

986

uagguugaug gcaugcacua ugcgcgagcg caacca 36

987

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

987

accaaugaug gcaugcacua ugcgcgauuc cuaggu 36

988

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

988

uuugaugaug gcaugcacua ugcgcgauga ccaaca 36

989

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

989

gugguugaug gcaugcacua ugcgcgauuu uuaaug 36

990

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

990

aauuuugaug gcaugcacua ugcgcgauua aaagag 36

991

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

991

auaaaugaug gcaugcacua ugcgcgauuu aaaagu 36

992

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

992

acuccugaug gcaugcacua ugcgcgauaa acauuu 36

993

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

993

cagcaugaug gcaugcacua ugcgcgauac uccuau 36

994

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

994

cacagugaug gcaugcacua ugcgcgacau acuccu 36

995

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

995

cuucaugaug gcaugcacua ugcgcgagca cauacu 36

996

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

996

cacuuugaug gcaugcacua ugcgcgacag cacaua 36

997

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

997

uagauugaug gcaugcacua ugcgcgacuu cacagc 36

998

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

998

uauuaugaug gcaugcacua ugcgcgaaau uuuaga 36

999

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

999

aaaaaugaug gcaugcacua ugcgcgauua caaauu 36

1000

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1000

caugaugaug gcaugcacua ugcgcgaaaa auauua 36

1001

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1001

caguuugaug gcaugcacua ugcgcgauga caaaaa 36

1002

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1002

uaguaugaug gcaugcacua ugcgcgaguu caugac 36

1003

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1003

cauuaugaug gcaugcacua ugcgcgaaua auuagg 36

1004

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1004

uauuaugaug gcaugcacua ugcgcgauua caauaa 36

1005

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1005

auuuuugaug gcaugcacua ugcgcgauua cauuac 36

1006

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1006

guaacugaug gcaugcacua ugcgcgauuu uuauua 36

1007

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1007

auaguugaug gcaugcacua ugcgcgacug uaacua 36

1008

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1008

acacuugaug gcaugcacua ugcgcgauag ucacug 36

1009

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1009

auacaugaug gcaugcacua ugcgcgacuc auaguc 36

1010

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1010

aaauaugaug gcaugcacua ugcgcgacac ucauag 36

1011

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1011

auuugugaug gcaugcacua ugcgcgauga auaaau 36

1012

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1012

caguuugaug gcaugcacua ugcgcgaaau uugcau 36

1013

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1013

gcaaaugaug gcaugcacua ugcgcgaguu caaauu 36

1014

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1014

cggggugaug gcaugcacua ugcgcgaaac aguuca 36

1015

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1015

cauuuugaug gcaugcacua ugcgcggggg caaaca 36

1016

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1016

auaucugaug gcaugcacua ugcgcgauuu cggggc 36

1017

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1017

auccaugaug gcaugcacua ugcgcgaucc auuucg 36

1018

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1018

guaucugaug gcaugcacua ugcgcgauau ccauuu 36

1019

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1019

uaaagugaug gcaugcacua ugcgcgaucc auaucc 36

1020

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1020

uggcuugaug gcaugcacua ugcgcgauaa aguauc 36

1021

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1021

gugucugaug gcaugcacua ugcgcgaugg cuuaua 36

1022

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1022

uauacugaug gcaugcacua ugcgcgauag ugucua 36

1023

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1023

acuggugaug gcaugcacua ugcgcgauac uauagu 36

1024

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1024

agauuugaug gcaugcacua ugcgcgacug guauac 36

1025

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1025

agcugugaug gcaugcacua ugcgcgauaa aagauu 36

1026

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1026

ucuaaugaug gcaugcacua ugcgcgaagc ugcaua 36

1027

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1027

cacagugaug gcaugcacua ugcgcgaccu uuuaga 36

1028

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1028

auccaugaug gcaugcacua ugcgcgagca ccuuuu 36

1029

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1029

cauaaugaug gcaugcacua ugcgcgaucc acagca 36

1030

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1030

cuuuaugaug gcaugcacua ugcgcgauaa uaucca 36

1031

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1031

gcaaaugaug gcaugcacua ugcgcgacgc cuuuac 36

1032

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1032

uuaagugaug gcaugcacua ugcgcgaaac acgccu 36

1033

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1033

cuaaaugaug gcaugcacua ugcgcgaugg aaaauu 36

1034

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1034

uuuugugaug gcaugcacua ugcgcgaucu acuucu 36

1035

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1035

aaaggugaug gcaugcacua ugcgcgagau uuguuu 36

1036

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1036

uuuguugaug gcaugcacua ugcgcgauaa aggcag 36

1037

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1037

uauccugaug gcaugcacua ugcgcgauuu uuuugu 36

1038

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1038

aauguugaug gcaugcacua ugcgcgaucc uauuuu 36

1039

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1039

uaccuugaug gcaugcacua ugcgcgauug auaaaa 36

1040

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1040

uguauugaug gcaugcacua ugcgcgaauu accuua 36

1041

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1041

uugugugaug gcaugcacua ugcgcgauca auuacc 36

1042

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1042

caaguugaug gcaugcacua ugcgcgaccu guugug 36

1043

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1043

uccauugaug gcaugcacua ugcgcgauua auguug 36

1044

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1044

auuucugaug gcaugcacua ugcgcgauua uuaaug 36

1045

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1045

ucaauugaug gcaugcacua ugcgcgauuu ccauua 36

1046

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1046

cuauuugaug gcaugcacua ugcgcgaauu auuucc 36

1047

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1047

cuaacugaug gcaugcacua ugcgcgauuc aauuau 36

1048

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1048

acauaugaug gcaugcacua ugcgcgauaa cuaacu 36

1049

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1049

auuaaugaug gcaugcacua ugcgcgauac auaacu 36

1050

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1050

acuggugaug gcaugcacua ugcgcgauua acauac 36

1051

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1051

ggaguugaug gcaugcacua ugcgcgauua cuucug 36

1052

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1052

auaugugaug gcaugcacua ugcgcgaugg agucau 36

1053

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1053

aauaaugaug gcaugcacua ugcgcgaugu auggag 36

1054

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1054

guaguugaug gcaugcacua ugcgcgauag aaauaa 36

1055

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1055

aacguugaug gcaugcacua ugcgcgaugg cuaggc 36

1056

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1056

aacggugaug gcaugcacua ugcgcgaugg cuaggc 36

1057

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1057

aacguugaug gcaugcacua ugcgcggugg cuaggc 36

1058

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1058

aacguugaug gcaugcacua ugcgcguugg cuaggc 36

1059

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1059

aacgaugaug gcaugcacua ugcgcgaugg cuaggc 36

1060

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1060

aacgaugaug gcaugcacua ugcgcggugg cuaggc 36

1061

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1061

aacggugaug gcaugcacua ugcgcggugg cuaggc 36

1062

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1062

aacggugaug gcaugcacua ugcgcguugg cuaggc 36

1063

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1063

aacgaugaug gcaugcacua ugcgcguugg cuaggc 36

1064

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1064

aacgcugaug gcaugcacua ugcgcggugg cuaggc 36

1065

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1065

aacgcugaug gcaugcacua ugcgcgaugg cuaggc 36

1066

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1066

aacguugaug gcaugcacua ugcgcgcugg cuaggc 36

1067

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1067

aacggugaug gcaugcacua ugcgcgcugg cuaggc 36

1068

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1068

aacgcugaug gcaugcacua ugcgcguugg cuaggc 36

1069

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1069

aacgaugaug gcaugcacua ugcgcgcugg cuaggc 36

1070

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1070

aacgcugaug gcaugcacua ugcgcgcugg cuaggc 36

1071

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1071

agcugugaug gcaugcacua ugcgcgaucg ucaaggn 37

1072

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1072

gaucaugaug gcaugcacua ugcgcgauuc guccacn 37

1073

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1073

uucucugaug gcaugcacua ugcgcgauca auuacun 37

1074

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1074

gagaaugaug gcaugcacua ugcgcgaucc aagagan 37

1075

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1075

ucccuugaug gcaugcacua ugcgcgauug cacugun 37

1076

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1076

guccuugaug gcaugcacua ugcgcgaugu acuggun 37

1077

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1077

aguauugaug gcaugcacua ugcgcgauuu auggcan 37

1078

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1078

agguaugaug gcaugcacua ugcgcgaucu ucagagn 37

1079

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1079

aggacugaug gcaugcacua ugcgcgauag guacaun 37

1080

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1080

aaucaugaug gcaugcacua ugcgcgauuu auuuccn 37

1081

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1081

aauucugaug gcaugcacua ugcgcgauaa cuucuun 37

1082

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1082

ggcauugaug gcaugcacua ugcgcgauca acacccn 37

1083

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1083

gaaggugaug gcaugcacua ugcgcgauca ucaacan 37

1084

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1084

uaaugugaug gcaugcacua ugcgcgauag aaggcan 37

1085

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1085

uuuacugaug gcaugcacua ugcgcgaucu uugcucn 37

1086

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1086

auaagugaug gcaugcacua ugcgcgauuu aagguan 37

1087

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1087

acaggugaug gcaugcacua ugcgcgauug cuaguun 37

1088

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1088

aacugugaug gcaugcacua ugcgcgaugc accaaan 37

1089

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1089

accaaugaug gcaugcacua ugcgcgauuc acacuun 37

1090

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1090

agcuuugaug gcaugcacua ugcgcgauua auuugun 37

1091

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1091

uaaucugaug gcaugcacua ugcgcgauuu augugan 37

1092

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1092

aagccugaug gcaugcacua ugcgcgauaa auuugun 37

1093

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1093

aucauugaug gcaugcacua ugcgcgauca ggaagcn 37

1094

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1094

agaauugaug gcaugcacua ugcgcgauca ucaggan 37

1095

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1095

acauuugaug gcaugcacua ugcgcgauca gggaugn 37

1096

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1096

cuuuaugaug gcaugcacua ugcgcgauuc aucaggn 37

1097

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1097

guuucugaug gcaugcacua ugcgcgauug ccuugun 37

1098

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1098

ggccuugaug gcaugcacua ugcgcgauaa uaguuun 37

1099

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1099

aaagcugaug gcaugcacua ugcgcgauua ggagucn 37

1100

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1100

aauccugaug gcaugcacua ugcgcgauuc auacugn 37

1101

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1101

guugcugaug gcaugcacua ugcgcgauaa uaauccn 37

1102

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1102

uaagcugaug gcaugcacua ugcgcgauaa cuggccn 37

1103

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1103

cucucugaug gcaugcacua ugcgcgauga aagcucn 37

1104

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1104

cagucugaug gcaugcacua ugcgcgaugc ugugaan 37

1105

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1105

caaugugaug gcaugcacua ugcgcgaucg uacaacn 37

1106

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1106

ugagcugaug gcaugcacua ugcgcgaucc aaacugn 37

1107

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1107

cacuuugaug gcaugcacua ugcgcgauug uuuaaan 37

1108

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1108

guguuugaug gcaugcacua ugcgcgaugc aauguun 37

1109

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1109

uuaaaugaug gcaugcacua ugcgcgaugg aucagan 37

1110

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1110

caugcugaug gcaugcacua ugcgcgaucu cacuucn 37

1111

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1111

cucacugaug gcaugcacua ugcgcgaugc caucucn 37

1112

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1112

acaccugaug gcaugcacua ugcgcgaucu agaaccn 37

1113

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1113

uuuaaugaug gcaugcacua ugcgcgauga agaaaun 37

1114

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1114

uggaaugaug gcaugcacua ugcgcgauaa aucacan 37

1115

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1115

auccuugaug gcaugcacua ugcgcgaugu aaauggn 37

1116

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1116

aacugugaug gcaugcacua ugcgcgauca agucaun 37

1117

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1117

aaucuugaug gcaugcacua ugcgcgaugg uuagggn 37

1118

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1118

ggagaugaug gcaugcacua ugcgcgaucc acagcan 37

1119

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1119

aacuuugaug gcaugcacua ugcgcgaugg agauaun 37

1120

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1120

uagggugaug gcaugcacua ugcgcgauuu cugaugn 37

1121

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1121

cccuuugaug gcaugcacua ugcgcgaugg uaucugn 37

1122

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1122

caaagugaug gcaugcacua ugcgcgauca gccaccn 37

1123

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1123

cuauuugaug gcaugcacua ugcgcgauac cagggun 37

1124

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1124

cauugugaug gcaugcacua ugcgcgauga agauuun 37

1125

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1125

agcuuugaug gcaugcacua ugcgcgauga auuaaan 37

1126

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1126

cacugugaug gcaugcacua ugcgcgauuc cagccun 37

1127

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1127

agguuugaug gcaugcacua ugcgcgauga ggccaan 37

1128

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1128

auaaaugaug gcaugcacua ugcgcgauuu gcugaan 37

1129

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1129

acuggugaug gcaugcacua ugcgcgaucu gguaggn 37

1130

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1130

uaccaugaug gcaugcacua ugcgcgauac ccagugn 37

1131

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1131

gauacugaug gcaugcacua ugcgcgauau acccagn 37

1132

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1132

gggauugaug gcaugcacua ugcgcgaugu cucuugn 37

1133

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1133

ggucgugaug gcaugcacua ugcgcgauac caaaggn 37

1134

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1134

cguguugaug gcaugcacua ugcgcgaucu cugggun 37

1135

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1135

auacgugaug gcaugcacua ugcgcgaucg uguuaun 37

1136

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1136

acaauugaug gcaugcacua ugcgcgauag agcuggn 37

1137

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1137

aaguuugaug gcaugcacua ugcgcgauuc cuuuaan 37

1138

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1138

acaguugaug gcaugcacua ugcgcgaugc caaauan 37

1139

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1139

uuacaugaug gcaugcacua ugcgcgauuu gggucan 37

1140

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1140

uggaaugaug gcaugcacua ugcgcgauua cacauun 37

1141

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1141

uuacuugaug gcaugcacua ugcgcgaugc agagaan 37

1142

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1142

cuguuugaug gcaugcacua ugcgcgauuu guacccn 37

1143

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1143

uuucaugaug gcaugcacua ugcgcgauag caauucn 37

1144

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1144

auggcugaug gcaugcacua ugcgcgauuu cuuucun 37

1145

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1145

ugaagugaug gcaugcacua ugcgcgaugg ccauuun 37

1146

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1146

augccugaug gcaugcacua ugcgcgaucu acaucan 37

1147

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1147

guucaugaug gcaugcacua ugcgcgauaa agguaan 37

1148

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1148

uaaacugaug gcaugcacua ugcgcgauuc aaaguun 37

1149

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1149

acaaaugaug gcaugcacua ugcgcgaugu uaaugcn 37

1150

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1150

ugcuaugaug gcaugcacua ugcgcgauuc uuccacn 37

1151

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1151

ucugcugaug gcaugcacua ugcgcgauau ucuuccn 37

1152

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1152

uacaaugaug gcaugcacua ugcgcgauac gucugcn 37

1153

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1153

gggaaugaug gcaugcacua ugcgcgauuc acucaan 37

1154

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1154

auuccugaug gcaugcacua ugcgcgaugc agugugn 37

1155

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1155

caugcugaug gcaugcacua ugcgcgaucc aguauun 37

1156

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1156

gaauuugaug gcaugcacua ugcgcgaugc uauccan 37

1157

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1157

acagcugaug gcaugcacua ugcgcgauuc aguuucn 37

1158

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1158

aucauugaug gcaugcacua ugcgcgaucc caaacan 37

1159

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1159

ccuauugaug gcaugcacua ugcgcgauua ucccaan 37

1160

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1160

cucaaugaug gcaugcacua ugcgcgauaa cugcagn 37

1161

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1161

augugugaug gcaugcacua ugcgcgaugu uucagun 37

1162

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1162

cugcaugaug gcaugcacua ugcgcgauga cccacan 37

1163

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1163

cacugugaug gcaugcacua ugcgcgauau gacccan 37

1164

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1164

accaaugaug gcaugcacua ugcgcgauuc cuaggun 37

1165

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1165

uuugaugaug gcaugcacua ugcgcgauga ccaacan 37

1166

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1166

cagcaugaug gcaugcacua ugcgcgauac uccuaun 37

1167

›DNA

Artificial Sequence

Description of Artificial Sequence Selection

Primer 1

1167

tggtgcaagc ttaatacgac tcactatagg gagactgtct agatcatgag gatgct 56

1168

›DNA

Artificial Sequence

Description of Artificial Sequence Selection

Primer 2

1168

tctcggatcc tgcagatcat nnnnnnnnnn nnnnnnnnnn nnaggattag catcctcat 59

1169

›DNA

Artificial Sequence

Description of Artificial Sequence Reverse

transcription primer

1169

tctcggatcc tgcagatcat 20

1170

›DNA

Artificial Sequence

Description of Artificial Sequence PCR primer

1170

tggtgcaagc ttaatacgac tca 23

1171

›RNA

Artificial Sequence

Description of Artificial Sequence

Miscellaneous substrate

1171

nnnnuhnnnn n 11

1172

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1172

nnnnncugan gagnnnnnnc gaaannnn 28

1173

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1173

agaucgucnn nngucuaauc cucugaugag cgcaagcgaa acgaucu 47

1174

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1174

agaucaugag gagucuaauc cunnnnnnnn nnnnnnnnnn nnnnaugauc u 51

1175

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1175

gggagacugu cuagaucaug aggagucuaa uccunnnnnn nnnnnnnnnn nnnnnnauga 60

ucugcagga 69

1176

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1176

cugaugagcg caagcgaa 18

1177

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1177

ggaaucagcc ugacaccggc cc 22

1178

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1178

ggcauccccg gcauggugcg cg 22

1179

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1179

agcauuaccc ggcuggugcg cg 22

1180

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1180

gcaucacggg gcaaucugcg cg 22

1181

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1181

agcaucaccc ggauggugcg cg 22

1182

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1182

agcaucaccc ggcuggugcg cg 22

1183

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1183

abcguccacg gcaucgagcg cg 22

1184

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1184

ugauggcuug cacuaagcgc g 21

1185

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1185

ugauggcaug cacuaugcgc g 21

1186

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1186

ugauggcaug caggaugcgc g 21

1187

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1187

ugauggcaug caccaugcgc g 21

1188

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1188

ugaucggaug caccaugcgc g 21

1189

›RNA

Artificial Sequence

Description of Artificial Sequence

Self-cleaving Enzymatic Nucleic Acid

1189

ugggccgauc gcaagggcgc g 21

1190

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1190

gggagacugu cuagaucaug aggaugcuaa uccuugaugg caugcacuau gcgcgaugau 60

cugcaggauc cgaga 75

1191

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1191

auccuugaug gcaugcacua ugcgcgauga ucugca 36

1192

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1191

1192

ugcagaucau gaggau 16

1193

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1193

auccuugaug gcaugcacua ugcgcgauga cgcug 35

1194

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1193

1194

cagcgucaug aggau 15

1195

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1195

auccuugaug gcaugcacua ugcgcgauga cgcuga 36

1196

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1195

1196

ucagcgucau gaggau 16

1197

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1197

cccuugaugg caugcacuau gcgcgauga 29

1198

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1197

1198

ucaugaggg 9

1199

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1199

auccuugaug gcaugcacua ugcgcgauga cgcugan 37

1200

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1199

1200

ucagcgucau gaggau 16

1201

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1201

auccuugaug gcaugcacua ugcgcgauga cgcugan 37

1202

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1201

1202

ucagcgucau gaggau 16

1203

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1203

auccuugaug gcaugcacua ugcgcgauga cgcuga 36

1204

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1203

1204

ucagcgucau gaggau 16

1205

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1205

auccuugaug gcaugcacua ugcgcgauga cgcugan 37

1206

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1205

1206

ucagcgucau gaggau 16

1207

›RNA

Artificial Sequence

Description of Artificial Sequence Enzymatic

Nucleic Acid

1207

nnnnuugaug gcaugcacua ugcgcgannn nnnnnnn 37

1208

›RNA

Artificial Sequence

Description of Artificial Sequence Substrate

Nucleic Acid for SEQ ID NO 1207

1208

nnnnnnnnnu gannnn 16

›Tables in the description — 5

TABLE I — Wait * Wait time does not include contact time during delivery.

Reagent	Equivalents	Amount	Wait Time*	Time*
A. 2.5 μmol Synthesis Cycle ABI 394 Instrument
			2′-O-methyl	RNA
Phosphoramidites	6.5	163 μL	2.5 min	7.5
S-Ethyl Tetrazole	23.8	238 μL	2.5 min	7.5
Acetic Anhydride	100	233 μL	5 sec	5 sec
N-Methyl Imidazole	186	233 μL	5 sec	5 sec
TCA	110.1	2.3 mL	21 sec	21 sec
Iodine	11.2	1.7 mL	45 sec	45 sec
Acetonitrile	NA	6.67 mL	NA	NA
B. 0.2 μmol Synthesis Cycle ABI 394 Instrument
			2′-O-methyl	RNA
Phosphoramidites	15	31 μL	233 sec	465 sec
S-Ethyl Tetrazole	38.7	31 μL	233 min	465 sec
Acetic Anhydride	655	124 μL	5 sec	5 sec
N-Methyl Imidazole	1245	124 μL	5 sec	5 sec
TCA	700	732 μL	10 sec	10 sec
Iodine	20.6	244 μL	15 sec	15 sec
Acetonitrile	NA	2.64 mL	NA	NA
C. 0.2 μmol Synthesis Cycle 96 well Instrument
	2′-O-methyl/	2′-O-methyl/
	Ribo	Ribo	2′-O-methyl	Ribo
Phosphoramidites	33/66	60/120 μL	233 sec	465 sec
S-Ethyl Tetrazole	75/150	60/120 μL	233 min	465 sec
Acetic Anhydride	50/50	50/50 μL	10 sec	10 sec
N-Methyl Imidazole	502/502	50/50 μL	10 sec	10 sec
TCA	16,000/	500/500	15 sec	15 sec
	16,000	μL
Iodine	6.8/6.8	80/80 μL	30 sec	30 sec
Acetonitrile	NA	850/850	NA	NA
		μL

TABLE II — Human K-ras Ribozyme and Target Sequence

Nt.		Seq. ID		Seq. ID
Position	Substrate Sequence	Nos.	Ribozyme Sequence	Nos.
16	GGCGGCGGCC G CGGCG	1	CGCCG UGAUGGCAUGCACUAUGCGCG GGCCGCCGCC	528
57	UGGCGGCGGC G AAGGU	2	ACCUU UGAUGGCAUGCACUAUGCGCG GCCGCCGCCA	529
94	CCCGGCCCCC G CCAUU	3	AAUGG UGAUGGCAUGCACUAUGCGCG GGGGGCCGGG	530
113	GACUGGGAGC G AGCGC	4	GCGCU UGAUGGCAUGCACUAUGCGCG GCUCCCAGUC	531
117	GGGAGCGAGC G CGGCG	5	CGCCG UGAUGGCAUGCACUAUGCGCG GCUCGCUCCC	532
122	CGAGCGCGGC G CAGGC	6	GCCUG UGAUGGCAUGCACUAUGCGCG GCCGCGCUCG	533
131	CGCAGGCACU G AAGGC	7	GCCUU UGAUGGCAUGCACUAUGCGCG AGUGCCUGCG	534
171	GCUCCCAGGU G CGGGA	8	UCCCG UGAUGGCAUGCACUAUGCGCG ACCUGGGAGC	535
186	AGAGAGGCCU G CUGAA	9	UUCAG UGAUGGCAUGCACUAUGCGCG AGGCCUCUCU	536
189	GAGGCCUGCU G AAAAU	10	AUUUU UGAUGGCAUGCACUAUGCGCG AGCAGGCCUC	537
195	UGCUGAAAAU G ACUGA	11	UCAGU UGAUGGCAUGCACUAUGCGCG AUUUUCAGCA	538
199	GAAAAUGACU G AAUAU	12	AUAUU UGAUGGCAUGCACUAUGCGCG AGUCAUUUUC	539
203	AUGACUGAAU A UAAAC	13	GUUUA UGAUGGCAUGCACUAUGCGCG AUUCAGUCAU	540
205	GACUGAAUAU A AACUU	14	AAGUU UGAUGGCAUGCACUAUGCGCG AUAUUCAGUC	541
211	AUAUAAACUU G UGGUA	15	UACCA UGAUGGCAUGCACUAUGCGCG AAGUUUAUAU	542
227	GUUGGAGCUU G UGGCG	16	CGCCA UGAUGGCAUGCACUAUGCGCG AAGCUCCAAC	543
244	AGGCAAGAGU G CCUUG	17	CAAGG UGAUGGCAUGCACUAUGCGCG ACUCUUGCCU	544
249	AGAGUGCCUU G ACGAU	18	AUCGU UGAUGGCAUGCACUAUGCGCG AAGGCACUCU	545
252	GUGCCUUGAC G AUACA	19	UGUAU UGAUGGCAUGCACUAUGCGCG GUCAAGGCAC	546
255	CCUUGACGAU A CAGCU	20	AGCUG UGAUGGCAUGCACUAUGCGCG AUCGUCAAGG	547
277	GAAUCAUUUU G UGGAC	21	GUCCA UGAUGGCAUGCACUAUGCGCG AAAAUGAUUC	548
283	UUUUGUGGAC G AAUAU	22	AUAUU UGAUGGCAUGCACUAUGCGCG GUCCACAAAA	549
287	GUGGACGAAU A UGAUC	23	GAUCA UGAUGGCAUGCACUAUGCGCG AUUCGUCCAC	550
289	GGACGAAUAU G AUCCA	24	UGGAU UGAUGGCAUGCACUAUGCGCG AUAUUCGUCC	551
300	AUCCAACAAU A GAGGA	25	UCCUC UGAUGGCAUGCACUAUGCGCG AUUGUUGGAU	552
331	AGUAGUAAUU G AUGGA	26	UCCAU UGAUGGCAUGCACUAUGCGCG AAUUACUACU	553
334	AGUAAUUGAU G GAGAA	27	UUCUC UGAUGGCAUGCACUAUGCGCG AUCAAUUACU	554
344	GGAGAAACCU G UCUCU	28	AGAGA UGAUGGCAUGCACUAUGCGCG AGGUUUCUCC	555
355	UCUCUUGGAU A UUCUC	29	GAGAA UGAUGGCAUGCACUAUGCGCG AUCCAAGAGA	556
361	GGAUAUUCUC G ACACA	30	UGUGU UGAUGGCAUGCACUAUGCGCG GAGAAUAUCC	557
388	GGAGUACAGU G CAAUG	31	CAUUG UGAUGGCAUGCACUAUGCGCG ACUGUACUCC	558
393	ACAGUGCAAU G AGGGA	32	UCCCU UGAUGGCAUGCACUAUGCGCG AUUGCACUGU	559
408	ACCAGUACAU G AGGAC	33	GUCCU UGAUGGCAUGCACUAUGCGCG AUGUACUGGU	560
431	GGCUUUCUUU G UGUAU	34	AUACA UGAUGGCAUGCACUAUGCGCG AAAGAAAGCC	561
433	CUUUCUUUGU G UAUUU	35	AAAUA UGAUGGCAUGCACUAUGCGCG ACAAAGAAAG	562
439	UUGUGUAUUU G CCAUA	36	UAUGG UGAUGGCAUGCACUAUGCGCG AAAUACACAA	563
444	UAUUUGCCAU A AAUAA	37	UUAUU UGAUGGCAUGCACUAUGCGCG AUGGCAAAUA	564
448	UGCCAUAAAU A AUACU	38	AGUAU UGAUGGCAUGCACUAUGCGCG AUUUAUGGCA	565
451	CAUAAAUAAU A CUAAA	39	UUUAG UGAUGGCAUGCACUAUGCGCG AUUAUUUAUG	566
463	UAAAUCAUUU G AAGAU	40	AUCUU UGAUGGCAUGCACUAUGCGCG AAAUGAUUUA	567
469	AUUUGAAGAU A UUCAC	41	GUGAA UGAUGGCAUGCACUAUGCGCG AUCUUCAAAU	568
481	UCACCAUUAU A GAGAA	42	UUCUC UGAUGGCAUGCACUAUGCGCG AUAAUGGUGA	569
511	UAAGGACUCU G AAGAU	43	AUCUU UGAUGGCAUGCACUAUGCGCG AGAGUCCUUA	570
517	CUCUGAAGAU G UACCU	44	AGGUA UGAUGGCAUGCACUAUGCGCG AUCUUCAGAG	571
525	AUGUACCUAU G GUCCU	45	AGGAC UGAUGGCAUGCACUAUGCGCG AUAGGUACAU	572
541	AGUAGGAAAU A AAUGU	46	ACAUU UGAUGGCAUGCACUAUGCGCG AUUUCCUACU	573
545	GGAAAUAAAU G UGAUU	47	AAUCA UGAUGGCAUGCACUAUGCGCG AUUUAUUUCC	574
547	AAAUAAAUGU G AUUUG	48	CAAAU UGAUGGCAUGCACUAUGCGCG ACAUUUAUUU	575
552	AAUGUGAUUU G CCUUC	49	GAAGG UGAUGGCAUGCACUAUGCGCG AAAUCACAUU	576
604	AAGAAGUUAU G GAAUU	50	AAUUC UGAUGGCAUGCACUAUGCGCG AUAACUUCUU	577
619	UCCUUUUAUU G AAACA	51	UGUUU UGAUGGCAUGCACUAUGCGCG AAUAAAAGGA	578
646	AAGACAGGGU G UUGAU	52	AUCAA UGAUGGCAUGCACUAUGCGCG ACCCUGUCUU	579
649	ACAGGGUGUU G AUGAU	53	AUCAU UGAUGGCAUGCACUAUGCGCG AACACCCUGU	580
652	GGGUGUUGAU G AUGCC	54	GGCAU UGAUGGCAUGCACUAUGCGCG AUCAACACCC	581
655	UGUUGAUGAU G CCUUC	55	GAAGG UGAUGGCAUGCACUAUGCGCG AUCAUCAACA	582
664	UGCCUUCUAU A CAUUA	56	UAAUG UGAUGGCAUGCACUAUGCGCG AUAGAAGGCA	583
674	ACAUUAGUUC G AGAAA	57	UUUCU UGAUGGCAUGCACUAUGCGCG GAACUAAUGU	584
683	CGAGAAAUUC G AAAAC	58	GUUUU UGAUGGCAUGCACUAUGCGCG GAAUUUCUCG	585
691	UCGAAAACAU A AAGAA	59	UUCUU UGAUGGCAUGCACUAUGCGCG AUGUUUUCGA	586
702	AAGAAAAGAU G AGCAA	60	UUGCU UGAUGGCAUGCACUAUGCGCG AUCUUUUCUU	587
712	GAGCAAAGAU G GUAAA	61	UUUAC UGAUGGCAUGCACUAUGCGCG AUCUUUGCUC	588
746	AAGACAAAGU G UGUAA	62	UUACA UGAUGGCAUGCACUAUGCGCG ACUUUGUCUU	589
748	GACAAAGUGU G UAAUU	63	AAUUA UGAUGGCAUGCACUAUGCGCG ACACUUUGUC	590
756	GUGUAAUUAU G UAAAU	64	AUUUA UGAUGGCAUGCACUAUGCGCG AUAAUUACAC	591
762	UUAUGUAAAU A CAAUU	65	AAUUG UGAUGGCAUGCACUAUGCGCG AUUUACAUAA	592
769	AAUACAAUUU G UACUU	66	AAGUA UGAUGGCAUGCACUAUGCGCG AAAUUGUAUU	593
789	CUUAAGGCAU A CUAGU	67	ACUAG UGAUGGCAUGCACUAUGCGCG AUGCCUUAAG	594
811	GGUAAUUUUU G UACAU	68	AUGUA UGAUGGCAUGCACUAUGCGCG AAAAAUUACC	595
838	AUUAGCAUUU G UUUUA	69	UAAAA UGAUGGCAUGCACUAUGCGCG AAAUGCUAAU	596
865	UUUUUUUCCU G CUCCA	70	UGGAG UGAUGGCAUGCACUAUGCGCG AGGAAAAAAA	597
872	CCUGCUCCAU G CAGAC	71	GUCUG UGAUGGCAUGCACUAUGCGCG AUGGAGCAGG	598
879	CAUGCAGACU G UUAGC	72	GCUAA UGAUGGCAUGCACUAUGCGCG AGUCUGCAUG	599
898	UACCUUAAAU G CUUAU	73	AUAAG UGAUGGCAUGCACUAUGCGCG AUUUAAGGUA	600
912	AUUUUAAAAU G ACAGU	74	ACUGU UGAUGGCAUGCACUAUGCGCG AUUUUAAAAU	601
936	UUUUUUCCUC G AAGUG	75	CACUU UGAUGGCAUGCACUAUGCGCG GAGGAAAAAA	602
941	UCCUCGAAGU G CCAGU	76	ACUGG UGAUGGCAUGCACUAUGCGCG ACUUCGAGGA	603
968	UUUGGUUUUU G AACUA	77	UAGUU UGAUGGCAUGCACUAUGCGCG AAAAACCAAA	604
979	AACUAGCAAU G CCUGU	78	ACAGG UGAUGGCAUGCACUAUGCGCG AUUGCUAGUU	605
983	AGCAAUGCCU G UGAAA	79	UUUCA UGAUGGCAUGCACUAUGCGCG AGGCAUUGCU	606
985	CAAUGCCUGU G AAAAA	80	UUUUU UGAUGGCAUGCACUAUGCGCG ACAGGCAUUG	607
997	AAAAGAAACU G AAUAC	81	GUAUU UGAUGGCAUGCACUAUGCGCG AGUUUCUUUU	608
1001	GAAACUGAAU A CCUAA	82	UUAGG UGAUGGCAUGCACUAUGCGCG AUUCAGUUUC	609
1014	UAAGAUUUCU G UCUUG	83	CAAGA UGAUGGCAUGCACUAUGCGCG AGAAAUCUUA	610
1031	GGUUUUUGGU G CAUGC	84	GCAUG UGAUGGCAUGCACUAUGCGCG ACCAAAAACC	611
1035	UUUGGUGCAU G CAGUU	85	AACUG UGAUGGCAUGCACUAUGCGCG AUGCACCAAA	612
1041	GCAUGCAGUU G AUUAC	86	GUAAU UGAUGGCAUGCACUAUGCGCG AACUGCAUGC	613
1068	CUUACCAAGU G UGAAU	87	AUUCA UGAUGGCAUGCACUAUGCGCG ACUUGGUAAG	614
1070	UACCAAGUGU G AAUGU	88	ACAUU UGAUGGCAUGCACUAUGCGCG ACACUUGGUA	615
1074	AAGUGUGAAU G UUGGU	89	ACCAA UGAUGGCAUGCACUAUGCGCG AUUCACACUU	616
1080	GAAUGUUGGU G UGAAA	90	UUUCA UGAUGGCAUGCACUAUGCGCG ACCAACAUUC	617
1082	AUGUUGGUGU G AAACA	91	UGUUU UGAUGGCAUGCACUAUGCGCG ACACCAACAU	618
1095	ACAAAUUAAU G AAGCU	92	AGCUU UGAUGGCAUGCACUAUGCGCG AUUAAUUUGU	619
1104	UGAAGCUUUU G AAUCA	93	UGAUU UGAUGGCAUGCACUAUGCGCG AAAAGCUUCA	620
1120	UCCCUAUUCU G UGUUU	94	AAACA UGAUGGCAUGCACUAUGCGCG AGAAUAGGGA	621
1122	CCUAUUCUGU G UUUUA	95	UAAAA UGAUGGCAUGCACUAUGCGCG ACAGAAUAGG	622
1139	CUAGUCACAU A AAUGG	96	CCAUU UGAUGGCAUGCACUAUGCGCG AUGUGACUAG	623
1143	UCACAUAAAU G GAUUA	97	UAAUC UGAUGGCAUGCACUAUGCGCG AUUUAUGUGA	624
1165	AAUUUCAGUU G AGACC	98	GGUCU UGAUGGCAUGCACUAUGCGCG AACUGAAAUU	625
1189	GGUUUUUACU G AAACA	99	UGUUU UGAUGGCAUGCACUAUGCGCG AGUAAAAACC	626
1197	CUGAAACAUU G AGGGA	100	UCCCU UGAUGGCAUGCACUAUGCGCG AAUGUUUCAG	627
1214	ACAAAUUUAU G GGCUU	101	AAGCC UGAUGGCAUGCACUAUGCGCG AUAAAUUUGU	628
1223	UGGGCUUCCU G AUGAU	102	AUCAU UGAUGGCAUGCACUAUGCGCG AGGAAGCCCA	629
1226	GCUUCCUGAU G AUGAU	103	AUCAU UGAUGGCAUGCACUAUGCGCG AUCAGGAAGC	630
1229	UCCUGAUGAU G AUUCU	104	AGAAU UGAUGGCAUGCACUAUGCGCG AUCAUCAGGA	631
1247	UAGGCAUCAU G UCCUA	105	UAGGA UGAUGGCAUGCACUAUGCGCG AUGAUGCCUA	632
1254	CAUGUCCUAU A GUUUG	106	CAAAC UGAUGGCAUGCACUAUGCGCG AUAGGACAUG	633
1259	CCUAUAGUUU G UCAUC	107	GAUGA UGAUGGCAUGCACUAUGCGCG AAACUAUAGG	634
1268	UGUCAUCCCU G AUGAA	108	UUCAU UGAUGGCAUGCACUAUGCGCG AGGGAUGACA	635
1271	CAUCCCUGAU G AAUGU	109	ACAUU UGAUGGCAUGCACUAUGCGCG AUCAGGGAUG	636
1275	CCUGAUGAAU G UAAAG	110	CUUUA UGAUGGCAUGCACUAUGCGCG AUUCAUCAGG	637
1288	AAGUUACACU G UUCAC	111	GUGAA UGAUGGCAUGCACUAUGCGCG AGUGUAACUU	638
1303	CAAAGGUUUU G UCUCC	112	GGAGA UGAUGGCAUGCACUAUGCGCG AAAACCUUUG	639
1317	CCUUUCCACU G CUAUU	113	AAUAG UGAUGGCAUGCACUAUGCGCG AGUGGAAAGG	640
1329	UAUUAGUCAU G GUCAC	114	GUGAC UGAUGGCAUGCACUAUGCGCG AUGACUAAUA	641
1347	UCCCCAAAAU A UUAUA	115	UAUAA UGAUGGCAUGCACUAUGCGCG AUUUUGGGGA	642
1352	AAAAUAUUAU A UUUUU	116	AAAAA UGAUGGCAUGCACUAUGCGCG AUAAUAUUUU	643
1363	UUUUUUCUAU A AAAAG	117	CUUUU UGAUGGCAUGCACUAUGCGCG AUAGAAAAAA	644
1377	AGAAAAAAAU G GAAAA	118	UUUUC UGAUGGCAUGCACUAUGCGCG AUUUUUUUCU	645
1398	ACAAGGCAAU G GAAAC	119	GUUUC UGAUGGCAUGCACUAUGCGCG AUUGCCUUGU	646
1410	AAACUAUUAU A AGGCC	120	GGCCU UGAUGGCAUGCACUAUGCGCG AUAAUAGUUU	647
1436	CACAUUAGAU A AAUUA	121	UAAUU UGAUGGCAUGCACUAUGCGCG AUCUAAUGUG	648
1446	AAAUUACUAU A AAGAC	122	GUCUU UGAUGGCAUGCACUAUGCGCG AUAGUAAUUU	649
1459	GACUCCUAAU A GCUUU	123	AAAGC UGAUGGCAUGCACUAUGCGCG AUUAGGAGUC	650
1470	GCUUUUUCCU G UUAAG	124	CUUAA UGAUGGCAUGCACUAUGCGCG AGGAAAAAGC	651
1489	GACCCAGUAU G AAUGG	125	CCAUU UGAUGGCAUGCACUAUGCGCG AUACUGGGUC	652
1493	CAGUAUGAAU G GGAUU	126	AAUCC UGAUGGCAUGCACUAUGCGCG AUUCAUACUG	653
1504	GGAUUAUUAU A GCAAC	127	GUUGC UGAUGGCAUGCACUAUGCGCG AUAAUAAUCC	654
1524	UUGGGGCUAU A UUUAC	128	GUAAA UGAUGGCAUGCACUAUGCGCG AUAGCCCCAA	655
1532	AUAUUUACAU G CUACU	129	AGUAG UGAUGGCAUGCACUAUGCGCG AUGUAAAUAU	656
1548	AAAUUUUUAU A AUAAU	130	AUUAU UGAUGGCAUGCACUAUGCGCG AUAAAAAUUU	657
1551	UUUUUAUAAU A AUUGA	131	UCAAU UGAUGGCAUGCACUAUGCGCG AUUAUAAAAA	658
1555	UAUAAUAAUU G AAAAG	132	CUUUU UGAUGGCAUGCACUAUGCGCG AAUUAUUAUA	659
1575	UAACAAGUAU A AAAAA	133	UUUUU UGAUGGCAUGCACUAUGCGCG AUACUUGUUA	660
1589	AAAUUCUCAU A GGAAU	134	AUUCC UGAUGGCAUGCACUAUGCGCG AUGAGAAUUU	661
1600	GGAAUUAAAU G UAGUC	135	GACUA UGAUGGCAUGCACUAUGCGCG AUUUAAUUCC	662
1611	UAGUCUCCCU G UGUCA	136	UGACA UGAUGGCAUGCACUAUGCGCG AGGGAGACUA	663
1613	GUCUCCCUGU G UCAGA	137	UCUGA UGAUGGCAUGCACUAUGCGCG ACAGGGAGAC	664
1621	GUGUCAGACU G CUCUU	138	AAGAG UGAUGGCAUGCACUAUGCGCG AGUCUGACAC	665
1631	GCUCUUUCAU A GUAUA	139	UAUAC UGAUGGCAUGCACUAUGCGCG AUGAAAGAGC	666
1636	UUCAUAGUAU A ACUUU	140	AAAGU UGAUGGCAUGCACUAUGCGCG AUACUAUGAA	667
1660	UCUUCAACUU G AGUCU	141	AGACU UGAUGGCAUGCACUAUGCGCG AAGUUGAAGA	668
1668	UUGAGUCUUU G AAGAU	142	AUCUU UGAUGGCAUGCACUAUGCGCG AAAGACUCAA	669
1674	CUUUGAAGAU A GUUUU	143	AAAAC UGAUGGCAUGCACUAUGCGCG AUCUUCAAAG	670
1686	UUUUAAUUCU G CUUGU	144	ACAAG UGAUGGCAUGCACUAUGCGCG AGAAUUAAAA	671
1690	AAUUCUGCUU G UGACA	145	UGUCA UGAUGGCAUGCACUAUGCGCG AAGCAGAAUU	672
1692	UUCUGCUUGU G ACAUU	146	AAUGU UGAUGGCAUGCACUAUGCGCG ACAAGCAGAA	673
1721	GGCCAGUUAU A GCUUA	147	UAAGC UGAUGGCAUGCACUAUGCGCG AUAACUGGCC	674
1733	CUUAUUAGGU G UUGAA	148	UUCAA UGAUGGCAUGCACUAUGCGCG ACCUAAUAAG	675
1736	AUUAGGUGUU G AAGAG	149	CUCUU UGAUGGCAUGCACUAUGCGCG AACACCUAAU	676
1751	GACCAAGGUU G CAAGC	150	GCUUG UGAUGGCAUGCACUAUGCGCG AACCUUGGUC	677
1765	GCCAGGCCCU G UGUGA	151	UCACA UGAUGGCAUGCACUAUGCGCG AGGGCCUGGC	678
1767	CAGGCCCUGU G UGAAC	152	GUUCA UGAUGGCAUGCACUAUGCGCG ACAGGGCCUG	679
1769	GGCCCUGUGU G AACCU	153	AGGUU UGAUGGCAUGCACUAUGCGCG ACACAGGGCC	680
1776	UGUGAACCUU G AGCUU	154	AAGCU UGAUGGCAUGCACUAUGCGCG AAGGUUCACA	681
1786	GAGCUUUCAU A GAGAG	155	CUCUC UGAUGGCAUGCACUAUGCGCG AUGAAAGCUC	682
1803	UUCACAGCAU G GACUG	156	CAGUC UGAUGGCAUGCACUAUGCGCG AUGCUGUGAA	683
1808	AGCAUGGACU G UGUGC	157	GCACA UGAUGGCAUGCACUAUGCGCG AGUCCAUGCU	684
1810	CAUGGACUGU G UGCCC	158	GGGCA UGAUGGCAUGCACUAUGCGCG ACAGUCCAUG	685
1812	UGGACUGUGU G CCCCA	159	UGGGG UGAUGGCAUGCACUAUGCGCG ACACAGUCCA	686
1827	ACGGUCAUCC G AGUGG	160	CCACU UGAUGGCAUGCACUAUGCGCG GGAUGACCGU	687
1835	CCGAGUGGUU G UACGA	161	UCGUA UGAUGGCAUGCACUAUGCGCG AACCACUCGG	688
1839	GUGGUUGUAC G AUGCA	162	UGCAU UGAUGGCAUGCACUAUGCGCG GUACAACCAC	689
1842	GUUGUACGAU G CAUUG	163	CAAUG UGAUGGCAUGCACUAUGCGCG AUCGUACAAC	690
1861	AGUCAAAAAU G GGGAG	164	CUCCC UGAUGGCAUGCACUAUGCGCG AUUUUUGACU	691
1886	CAGUUUGGAU A GCUCA	165	UGAGC UGAUGGCAUGCACUAUGCGCG AUCCAAACUG	692
1899	UCAACAAGAU A CAAUC	166	GAUUG UGAUGGCAUGCACUAUGCGCG AUCUUGUUGA	693
1912	AUCUCACUCU G UGGUG	167	CACCA UGAUGGCAUGCACUAUGCGCG AGAGUGAGAU	694
1923	UGGUGGUCCU G CUGAC	168	GUCAG UGAUGGCAUGCACUAUGCGCG AGGACCACCA	695
1926	UGGUCCUGCU G ACAAA	169	UUUGU UGAUGGCAUGCACUAUGCGCG AGCAGGACCA	696
1943	CAAGAGCAUU G CUUUU	170	AAAAG UGAUGGCAUGCACUAUGCGCG AAUGCUCUUG	697
1949	CAUUGCUUUU G UUUCU	171	AGAAA UGAUGGCAUGCACUAUGCGCG AAAAGCAAUG	698
1993	ACUUUUAAAU A UUAAC	172	GUUAA UGAUGGCAUGCACUAUGCGCG AUUUAAAAGU	699
2008	CUCAAAAGUU G AGAUU	173	AAUCU UGAUGGCAUGCACUAUGCGCG AACUUUUGAG	700
2027	GGGUGGUGGU G UGCCA	174	UGGCA UGAUGGCAUGCACUAUGCGCG ACCACCACCC	701
2029	GUGGUGGUGU G CCAAG	175	CUUGG UGAUGGCAUGCACUAUGCGCG ACACCACCAC	702
2059	UUUAAACAAU G AAGUG	176	CACUU UGAUGGCAUGCACUAUGCGCG AUUGUUUAAA	703
2064	ACAAUGAAGU G AAAAA	177	UUUUU UGAUGGCAUGCACUAUGCGCG ACUUCAUUGU	704
2124	AAUUAACAUU G CAUAA	178	UUAUG UGAUGGCAUGCACUAUGCGCG AAUGUUAAUU	705
2128	AACAUUGCAU A AACAC	179	GUGUU UGAUGGCAUGCACUAUGCGCG AUGCAAUGUU	706
2145	UUUCAAGUCU G AUCCA	180	UGGAU UGAUGGCAUGCACUAUGCGCG AGACUUGAAA	707
2152	UCUGAUCCAU A UUUAA	181	UUAAA UGAUGGCAUGCACUAUGCGCG AUGGAUCAGA	708
2159	CAUAUUUAAU A AUGCU	182	AGCAU UGAUGGCAUGCACUAUGCGCG AUUAAAUAUG	709
2162	AUUUAAUAAU G CUUUA	183	UAAAG UGAUGGCAUGCACUAUGCGCG AUUAUUAAAU	710
2172	GCUUUAAAAU A AAAAU	184	AUUUU UGAUGGCAUGCACUAUGCGCG AUUUUAAAGC	711
2178	AAAUAAAAAU A AAAAC	185	GUUUU UGAUGGCAUGCACUAUGCGCG AUUUUUAUUU	712
2193	CAAUCCUUUU G AUAAA	186	UUUAU UGAUGGCAUGCACUAUGCGCG AAAAGGAUUG	713
2196	UCCUUUUGAU A AAUUU	187	AAAUU UGAUGGCAUGCACUAUGCGCG AUCAAAAGGA	714
2207	AAUUUAAAAU G UUACU	188	AGUAA UGAUGGCAUGCACUAUGCGCG AUUUUAAAUU	715
2224	AUUUUAAAAU A AAUGA	189	UCAUU UGAUGGCAUGCACUAUGCGCG AUUUUAAAAU	716
2228	UAAAAUAAAU G AAGUG	190	CACUU UGAUGGCAUGCACUAUGCGCG AUUUAUUUUA	717
2233	UAAAUGAAGU G AGAUG	191	CAUCU UGAUGGCAUGCACUAUGCGCG ACUUCAUUUA	718
2238	GAAGUGAGAU G GCAUG	192	CAUGC UGAUGGCAUGCACUAUGCGCG AUCUCACUUC	719
2243	GAGAUGGCAU G GUGAG	193	CUCAC UGAUGGCAUGCACUAUGCGCG AUGCCAUCUC	720
2246	AUGGCAUGGU G AGGUG	194	CACCU UGAUGGCAUGCACUAUGCGCG ACCAUGCCAU	721
2251	AUGGUGAGGU G AAAGU	195	ACUUU UGAUGGCAUGCACUAUGCGCG ACCUCACCAU	722
2273	GGACUAGGUU G UUGGU	196	ACCAA UGAUGGCAUGCACUAUGCGCG AACCUAGUCC	723
2279	GGUUGUUGGU G ACUUA	197	UAAGU UGAUGGCAUGCACUAUGCGCG ACCAACAACC	724
2295	GGUUCUAGAU A GGUGU	198	ACACC UGAUGGCAUGCACUAUGCGCG AUCUAGAACC	725
2299	CUAGAUAGGU G UCUUU	199	AAAGA UGAUGGCAUGCACUAUGCGCG ACCUAUCUAG	726
2314	UUAGGACUCU G AUUUU	200	AAAAU UGAUGGCAUGCACUAUGCGCG AGAGUCCUAA	727
2320	CUCUGAUUUU G AGGAC	201	GUCCU UGAUGGCAUGCACUAUGCGCG AAAAUCAGAG	728
2350	AUUUCUUCAU G UUAAA	202	UUUAA UGAUGGCAUGCACUAUGCGCG AUGAAGAAAU	729
2397	UUUACACUAU G UGAUU	203	AAUCA UGAUGGCAUGCACUAUGCGCG AUAGUGUAAA	730
2399	UACACUAUGU G AUUUA	204	UAAAU UGAUGGCAUGCACUAUGCGCG ACAUAGUGUA	731
2406	UGUGAUUUAU A UUCCA	205	UGGAA UGAUGGCAUGCACUAUGCGCG AUAAAUCACA	732
2419	CCAUUUACAU A AGGAU	206	AUCCU UGAUGGCAUGCACUAUGCGCG AUGUAAAUGG	733
2425	ACAUAAGGAU A CACUU	207	AAGUG UGAUGGCAUGCACUAUGCGCG AUCCUUAUGU	734
2435	ACACUUAUUU G UCAAG	208	CUUGA UGAUGGCAUGCACUAUGCGCG AAAUAAGUGU	735
2454	AGCACAAUCU G UAAAU	209	AUUUA UGAUGGCAUGCACUAUGCGCG AGAUUGUGCU	736
2471	UUUAACCUAU G UUACA	210	UGUAA UGAUGGCAUGCACUAUGCGCG AUAGGUUAAA	737
2488	CAUCUUCAGU G CCAGU	211	ACUGG UGAUGGCAUGCACUAUGCGCG ACUGAAGAUG	738
2507	GGGCAAAAUU G UGCAA	212	UUGCA UGAUGGCAUGCACUAUGCGCG AAUUUUGCCC	739
2509	GCAAAAUUGU G CAAGA	213	UCUUG UGAUGGCAUGCACUAUGCGCG ACAAUUUUGC	740
2518	UGCAAGAGGU G AAGUU	214	AACUU UGAUGGCAUGCACUAUGCGCG ACCUCUUGCA	741
2527	UGAAGUUUAU A UUUGA	215	UCAAA UGAUGGCAUGCACUAUGCGCG AUAAACUUCA	742
2531	GUUUAUAUUU G AAUAU	216	AUAUU UGAUGGCAUGCACUAUGCGCG AAAUAUAAAC	743
2535	AUAUUUGAAU A UCCAU	217	AUGGA UGAUGGCAUGCACUAUGCGCG AUUCAAAUAU	744
2566	CUUCUUCCAU A UUAGU	218	ACUAA UGAUGGCAUGCACUAUGCGCG AUGGAAGAAG	745
2572	CCAUAUUAGU G UCAUC	219	GAUGA UGAUGGCAUGCACUAUGCGCG ACUAAUAUGG	746
2580	GUGUCAUCUU G CCUCC	220	GGAGG UGAUGGCAUGCACUAUGCGCG AAGAUGACAC	747
2599	CCUUCCACAU G CCCCA	221	UGGGG UGAUGGCAUGCACUAUGCGCG AUGUGGAAGG	748
2606	CAUGCCCCAU G ACUUG	222	CAAGU UGAUGGCAUGCACUAUGCGCG AUGGGGCAUG	749
2611	CCCAUGACUU G AUGCA	223	UGCAU UGAUGGCAUGCACUAUGCGCG AAGUCAUGGG	750
2614	AUGACUUGAU G CAGUU	224	AACUG UGAUGGCAUGCACUAUGCGCG AUCAAGUCAU	751
2625	CAGUUUUAAU A CUUGU	225	ACAAG UGAUGGCAUGCACUAUGCGCG AUUAAAACUG	752
2629	UUUAAUACUU G UAAUU	226	AAUUA UGAUGGCAUGCACUAUGCGCG AAGUAUUAAA	753
2646	CCCUAACCAU A AGAUU	227	AAUCU UGAUGGCAUGCACUAUGCGCG AUGGUUAGGG	754
2656	AAGAUUUACU G CUGCU	228	AGCAG UGAUGGCAUGCACUAUGCGCG AGUAAAUCUU	755
2659	AUUUACUGCU G CUGUG	229	CACAG UGAUGGCAUGCACUAUGCGCG AGCAGUAAAU	756
2662	UACUGCUGCU G UGGAU	230	AUCCA UGAUGGCAUGCACUAUGCGCG AGCAGCAGUA	757
2668	UGCUGUGGAU A UCUCC	231	GGAGA UGAUGGCAUGCACUAUGCGCG AUCCACAGCA	758
2676	AUAUCUCCAU G AAGUU	232	AACUU UGAUGGCAUGCACUAUGCGCG AUGGAGAUAU	759
2690	UUUUCCCACU G AGUCA	233	UGACU UGAUGGCAUGCACUAUGCGCG AGUGGGAAAA	760
2706	CAUCAGAAAU G CCCUA	234	UAGGG UGAUGGCAUGCACUAUGCGCG AUUUCUGAUG	761
2744	AAGAGAAUCU G ACAGA	235	UCUGU UGAUGGCAUGCACUAUGCGCG AGAUUCUCUU	762
2751	UCUGACAGAU A CCAUA	236	UAUGG UGAUGGCAUGCACUAUGCGCG AUCUGUCAGA	763
2756	CAGAUACCAU A AAGGG	237	CCCUU UGAUGGCAUGCACUAUGCGCG AUGGUAUCUG	764
2766	AAAGGGAUUU G ACCUA	238	UAGGU UGAUGGCAUGCACUAUGCGCG AAAUCCCUUU	765
2796	GGUGGUGGCU G AUGCU	239	AGCAU UGAUGGCAUGCACUAUGCGCG AGCCACCACC	766
2799	GGUGGCUGAU G CUUUG	240	CAAAG UGAUGGCAUGCACUAUGCGCG AUCAGCCACC	767
2804	CUGAUGCUUU G AACAU	241	AUGUU UGAUGGCAUGCACUAUGCGCG AAAGCAUCAG	768
2816	ACAUCUCUUU G CUGCC	242	GGCAG UGAUGGCAUGCACUAUGCGCG AAAGAGAUGU	769
2819	UCUCUUUGCU G CCCAA	243	UUGGG UGAUGGCAUGCACUAUGCGCG AGCAAAGAGA	770
2834	AUCCAUUAGC G ACAGU	244	ACUGU UGAUGGCAUGCACUAUGCGCG GCUAAUGGAU	771
2861	ACCCUGGUAU G AAUAG	245	CUAUU UGAUGGCAUGCACUAUGCGCG AUACCAGGGU	772
2865	UGGUAUGAAU A GACAG	246	CUGUC UGAUGGCAUGCACUAUGCGCG AUUCAUACCA	773
2900	AGAAUUUAAU A AAGAU	247	AUCUU UGAUGGCAUGCACUAUGCGCG AUUAAAUUCU	774
2906	UAAUAAAGAU A GUGCA	248	UGCAC UGAUGGCAUGCACUAUGCGCG AUCUUUAUUA	775
2909	UAAAGAUAGU G CAGAA	249	UUCUG UGAUGGCAUGCACUAUGCGCG ACUAUCUUUA	776
2936	GGUAAUCUAU A ACUAG	250	CUAGU UGAUGGCAUGCACUAUGCGCG AUAGAUUACC	777
2964	UAACAGUAAU A CAUUC	251	GAAUG UGAUGGCAUGCACUAUGCGCG AUUACUGUUA	778
2974	ACAUUCCAUU G UUUUA	252	UAAAA UGAUGGCAUGCACUAUGCGCG AAUGGAAUGU	779
2998	AAAUCUUCAU G CAAUG	253	CAUUG UGAUGGCAUGCACUAUGCGCG AUGAAGAUUU	780
3003	UUCAUGCAAU G AAAAA	254	UUUUU UGAUGGCAUGCACUAUGCGCG AUUGCAUGAA	781
3010	AAUGAAAAAU A CUUUA	255	UAAAG UGAUGGCAUGCACUAUGCGCG AUUUUUCAUU	782
3022	UUUAAUUCAU G AAGCU	256	AGCUU UGAUGGCAUGCACUAUGCGCG AUGAAUUAAA	783
3046	UUUUUUUGGU G UCAGA	257	UCUGA UGAUGGCAUGCACUAUGCGCG ACCAAAAAAA	784
3057	UCAGAGUCUC G CUCUU	258	AAGAG UGAUGGCAUGCACUAUGCGCG GAGACUCUGA	785
3063	UCUCGCUCUU G UCACC	259	GGUGA UGAUGGCAUGCACUAUGCGCG AAGAGCGAGA	786
3080	AGGCUGGAAU G CAGUG	260	CACUG UGAUGGCAUGCACUAUGCGCG AUUCCAGCCU	787
3088	AUGCAGUGGC G CCAUC	261	GAUGG UGAUGGCAUGCACUAUGCGCG GCCACUGCAU	788
3104	UCAGCUCACU G CAACC	262	GGUUG UGAUGGCAUGCACUAUGCGCG AGUGAGCUGA	789
3132	AGGUUCAAGC G AUUCU	263	AGAAU UGAUGGCAUGCACUAUGCGCG GCUUGAACCU	790
3141	CGAUUCUCGU G CCUCG	264	CGAGG UGAUGGCAUGCACUAUGCGCG ACGAGAAUCG	791
3154	UCGGCCUCCU G AGUAG	265	CUACU UGAUGGCAUGCACUAUGCGCG AGGAGGCCGA	792
3176	UUACAGGCGU G UGCAC	266	GUGCA UGAUGGCAUGCACUAUGCGCG ACGCCUGUAA	793
3178	ACAGGCGUGU G CACUA	267	UAGUG UGAUGGCAUGCACUAUGCGCG ACACGCCUGU	794
3200	ACUAAUUUUU G UAUUU	268	AAAUA UGAUGGCAUGCACUAUGCGCG AAAAAUUAGU	795
3229	GGUUUCACCU G UUGGC	269	GCCAA UGAUGGCAUGCACUAUGCGCG AGGUGAAACC	796
3247	GGCUGGUCUC G AACUC	270	GAGUU UGAUGGCAUGCACUAUGCGCG GAGACCAGCC	797
3255	UCGAACUCCU G ACCUC	271	GAGGU UGAUGGCAUGCACUAUGCGCG AGGAGUUCGA	798
3265	GACCUCAAGU G AUUCA	272	UGAAU UGAUGGCAUGCACUAUGCGCG ACUUGAGGUC	799
3287	UUGGCCUCAU A AACCU	273	AGGUU UGAUGGCAUGCACUAUGCGCG AUGAGGCCAA	800
3293	UCAUAAACCU G UUUUG	274	CAAAA UGAUGGCAUGCACUAUGCGCG AGGUUUAUGA	801
3298	AACCUGUUUU G CAGAA	275	UUCUG UGAUGGCAUGCACUAUGCGCG AAAACAGGUU	802
3322	UUCAGCAAAU A UUUAU	276	AUAAA UGAUGGCAUGCACUAUGCGCG AUUUGCUGAA	803
3329	AAUAUUUAUU G AGUGC	277	GCACU UGAUGGCAUGCACUAUGCGCG AAUAAAUAUU	804
3333	UUUAUUGAGU G CCUAC	278	GUAGG UGAUGGCAUGCACUAUGCGCG ACUCAAUAAA	805
3344	CCUACCAGAU G CCAGU	279	ACUGG UGAUGGCAUGCACUAUGCGCG AUCUGGUAGG	806
3354	GCCAGUCACC G CACAA	280	UUGUG UGAUGGCAUGCACUAUGCGCG GGUGACUGGC	807
3372	CACUGGGUAU A UGGUA	281	UACCA UGAUGGCAUGCACUAUGCGCG AUACCCAGUG	808
3374	CUGGGUAUAU G GUAUC	282	GAUAC UGAUGGCAUGCACUAUGCGCG AUAUACCCAG	809
3396	CAAGAGACAU A AUCCC	283	GGGAU UGAUGGCAUGCACUAUGCGCG AUGUCUCUUG	810
3416	CUUAGGUACU G CUAGU	284	ACUAG UGAUGGCAUGCACUAUGCGCG AGUACCUAAG	811
3422	UACUGCUAGU G UGGUC	285	GACCA UGAUGGCAUGCACUAUGCGCG ACUAGCAGUA	812
3429	AGUGUGGUCU G UAAUA	286	UAUUA UGAUGGCAUGCACUAUGCGCG AGACCACACU	813
3434	GGUCUGUAAU A UCUUA	287	UAAGA UGAUGGCAUGCACUAUGCGCG AUUACAGACC	814
3456	CCUUUGGUAU A CGACC	288	GGUCG UGAUGGCAUGCACUAUGCGCG AUACCAAAGG	815
3458	UUUGGUAUAC G ACCCA	289	UGGGU UGAUGGCAUGCACUAUGCGCG GUAUACCAAA	816
3469	ACCCAGAGAU A ACACG	290	CGUGU UGAUGGCAUGCACUAUGCGCG AUCUCUGGGU	817
3474	GAGAUAACAC G AUGCG	291	CGCAU UGAUGGCAUGCACUAUGCGCG GUGUUAUCUC	818
3477	AUAACACGAU G CGUAU	292	AUACG UGAUGGCAUGCACUAUGCGCG AUCGUGUUAU	819
3492	UUUUAGUUUU G CAAAG	293	CUUUG UGAUGGCAUGCACUAUGCGCG AAAACUAAAA	820
3514	UUUGGUCUCU G UGCCA	294	UGGCA UGAUGGCAUGCACUAUGCGCG AGAGACCAAA	821
3516	UGGUCUCUGU G CCAGC	295	GCUGG UGAUGGCAUGCACUAUGCGCG ACAGAGACCA	822
3527	CCAGCUCUAU A AUUGU	296	ACAAU UGAUGGCAUGCACUAUGCGCG AUAGAGCUGG	823
3531	CUCUAUAAUU G UUUUG	297	CAAAA UGAUGGCAUGCACUAUGCGCG AAUUAUAGAG	824
3536	UAAUUGUUUU G CUACG	298	CGUAG UGAUGGCAUGCACUAUGCGCG AAAACAAUUA	825
3541	GUUUUGCUAC G AUUCC	299	GGAAU UGAUGGCAUGCACUAUGCGCG GUAGCAAAAC	826
3550	CGAUUCCACU G AAACU	300	AGUUU UGAUGGCAUGCACUAUGCGCG AGUGGAAUCG	827
3560	GAAACUCUUC G AUCAA	301	UUGAU UGAUGGCAUGCACUAUGCGCG GAAGAGUUUC	828
3576	GCUACUUUAU G UAAAU	302	AUUUA UGAUGGCAUGCACUAUGCGCG AUAAAGUAGC	829
3591	UCACUUCAUU G UUUUA	303	UAAAA UGAUGGCAUGCACUAUGCGCG AAUGAAGUGA	830
3604	UUAAAGGAAU A AACUU	304	AAGUU UGAUGGCAUGCACUAUGCGCG AUUCCUUUAA	831
3610	GAAUAAACUU G AUUAU	305	AUAAU UGAUGGCAUGCACUAUGCGCG AAGUUUAUUC	832
3616	ACUUGAUUAU A UUGUU	306	AACAA UGAUGGCAUGCACUAUGCGCG AUAAUCAAGU	833
3619	UGAUUAUAUU G UUUUU	307	AAAAA UGAUGGCAUGCACUAUGCGCG AAUAUAAUCA	834
3636	UAUUUGGCAU A ACUGU	308	ACAGU UGAUGGCAUGCACUAUGCGCG AUGCCAAAUA	835
3640	UGGCAUAACU G UGAUU	309	AAUCA UGAUGGCAUGCACUAUGCGCG AGUUAUGCCA	836
3642	GCAUAACUGU G AUUCU	310	AGAAU UGAUGGCAUGCACUAUGCGCG ACAGUUAUGC	837
3663	GACAAUUACU G UACAC	311	GUGUA UGAUGGCAUGCACUAUGCGCG AGUAAUUGUC	838
3677	ACAUUAAGGU G UAUGU	312	ACAUA UGAUGGCAUGCACUAUGCGCG ACCUUAAUGU	839
3681	UAAGGUGUAU G UCAGA	313	UCUGA UGAUGGCAUGCACUAUGCGCG AUACACCUUA	840
3688	UAUGUCAGAU A UUCAU	314	AUGAA UGAUGGCAUGCACUAUGCGCG AUCUGACAUA	841
3694	AGAUAUUCAU A UUGAC	315	GUCAA UGAUGGCAUGCACUAUGCGCG AUGAAUAUCU	842
3697	UAUUCAUAUU G ACCCA	316	UGGGU UGAUGGCAUGCACUAUGCGCG AAUAUGAAUA	843
3706	UGACCCAAAU G UGUAA	317	UUACA UGAUGGCAUGCACUAUGCGCG AUUUGGGUCA	844
3708	ACCCAAAUGU G UAAUA	318	UAUUA UGAUGGCAUGCACUAUGCGCG ACAUUUGGGU	845
3713	AAUGUGUAAU A UUCCA	319	UGGAA UGAUGGCAUGCACUAUGCGCG AUUACACAUU	846
3728	AGUUUUCUCU G CAUAA	320	UUAUG UGAUGGCAUGCACUAUGCGCG AGAGAAAACU	847
3732	UUCUCUGCAU A AGUAA	321	UUACU UGAUGGCAUGCACUAUGCGCG AUGCAGAGAA	848
3745	UAAUUAAAAU A UACUU	322	AAGUA UGAUGGCAUGCACUAUGCGCG AUUUUAAUUA	849
3747	AUUAAAAUAU A CUUAA	323	UUAAG UGAUGGCAUGCACUAUGCGCG AUAUUUUAAU	850
3761	AAAAAUUAAU A GUUUU	324	AAAAC UGAUGGCAUGCACUAUGCGCG AUUAAUUUUU	851
3781	GGGUACAAAU A AACAG	325	CUGUU UGAUGGCAUGCACUAUGCGCG AUUUGUACCC	852
3788	AAUAAACAGU G CCUGA	326	UCAGG UGAUGGCAUGCACUAUGCGCG ACUGUUUAUU	853
3792	AACAGUGCCU G AACUA	327	UAGUU UGAUGGCAUGCACUAUGCGCG AGGCACUGUU	854
3823	AAACUUCUAU G UAAAA	328	UUUUA UGAUGGCAUGCACUAUGCGCG AUAGAAGUUU	855
3837	AAAUCACUAU G AUUUC	329	GAAAU UGAUGGCAUGCACUAUGCGCG AUAGUGAUUU	856
3844	UAUGAUUUCU G AAUUG	330	CAAUU UGAUGGCAUGCACUAUGCGCG AGAAAUCAUA	857
3849	UUUCUGAAUU G CUAUG	331	CAUAG UGAUGGCAUGCACUAUGCGCG AAUUCAGAAA	858
3854	GAAUUGCUAU G UGAAA	332	UUUCA UGAUGGCAUGCACUAUGCGCG AUAGCAAUUC	859
3856	AUUGCUAUGU G AAACU	333	AGUUU UGAUGGCAUGCACUAUGCGCG ACAUAGCAAU	860
3880	UUGGAACACU G UUUAG	334	CUAAA UGAUGGCAUGCACUAUGCGCG AGUGUUCCAA	861
3893	UAGGUAGGGU G UUAAG	335	CUUAA UGAUGGCAUGCACUAUGCGCG ACCCUACCUA	862
3903	GUUAAGACUU G ACACA	336	UGUGU UGAUGGCAUGCACUAUGCGCG AAGUCUUAAC	863
3938	AGAAAGAAAU G GCCAU	337	AUGGC UGAUGGCAUGCACUAUGCGCG AUUUCUUUCU	864
3944	AAAUGGCCAU A CUUCA	338	UGAAG UGAUGGCAUGCACUAUGCGCG AUGGCCAUUU	865
3956	UUCAGGAACU G CAGUG	339	CACUG UGAUGGCAUGCACUAUGCGCG AGUUCCUGAA	866
3961	GAACUGCAGU G CUUAU	340	AUAAG UGAUGGCAUGCACUAUGCGCG ACUGCAGUUC	867
3967	CAGUGCUUAU G AGGGG	341	CCCCU UGAUGGCAUGCACUAUGCGCG AUAAGCACUG	868
3975	AUGAGGGGAU A UUUAG	342	CUAAA UGAUGGCAUGCACUAUGCGCG AUCCCCUCAU	869
3988	UAGGCCUCUU G AAUUU	343	AAAUU UGAUGGCAUGCACUAUGCGCG AAGAGGCCUA	870
3996	UUGAAUUUUU G AUGUA	344	UACAU UGAUGGCAUGCACUAUGCGCG AAAAAUUCAA	871
3999	AAUUUUUGAU G UAGAU	345	AUCUA UGAUGGCAUGCACUAUGCGCG AUCAAAAAUU	872
4005	UGAUGUAGAU G GGCAU	346	AUGCC UGAUGGCAUGCACUAUGCGCG AUCUACAUCA	873
4041	UUACCUUUAU G UGAAC	347	GUUCA UGAUGGCAUGCACUAUGCGCG AUAAAGGUAA	874
4043	ACCUUUAUGU G AACUU	348	AAGUU UGAUGGCAUGCACUAUGCGCG ACAUAAAGGU	875
4050	UGUGAACUUU G AAUGG	349	CCAUU UGAUGGCAUGCACUAUGCGCG AAAGUUCACA	876
4054	AACUUUGAAU G GUUUA	350	UAAAC UGAUGGCAUGCACUAUGCGCG AUUCAAAGUU	877
4071	CAAAAGAUUU G UUUUU	351	AAAAA UGAUGGCAUGCACUAUGCGCG AAAUCUUUUG	878
4077	AUUUGUUUUU G UAGAG	352	CUCUA UGAUGGCAUGCACUAUGCGCG AAAAACAAAU	879
4110	UUCUAGAAAU A AAUGU	353	ACAUU UGAUGGCAUGCACUAUGCGCG AUUUCUAGAA	880
4114	AGAAAUAAAU G UUACC	354	GGUAA UGAUGGCAUGCACUAUGCGCG AUUUAUUUCU	881
4152	AAAAAUCCUU G UUGAA	355	UUCAA UGAUGGCAUGCACUAUGCGCG AAGGAUUUUU	882
4155	AAUCCUUGUU G AAGUU	356	AACUU UGAUGGCAUGCACUAUGCGCG AACAAGGAUU	883
4186	UAAAUUACAU A GACUU	357	AAGUC UGAUGGCAUGCACUAUGCGCG AUGUAAUUUA	884
4204	GCAUUAACAU G UUUGU	358	ACAAA UGAUGGCAUGCACUAUGCGCG AUGUUAAUGC	885
4208	UAACAUGUUU G UGGAA	359	UUCCA UGAUGGCAUGCACUAUGCGCG AAACAUGUUA	886
4218	GUGGAAGAAU A UAGCA	360	UGCUA UGAUGGCAUGCACUAUGCGCG AUUCUUCCAC	887
4220	GGAAGAAUAU A GCAGA	361	UCUGC UGAUGGCAUGCACUAUGCGCG AUAUUCUUCC	888
4231	GCAGACGUAU A UUGUA	362	UACAA UGAUGGCAUGCACUAUGCGCG AUACGUCUGC	889
4234	GACGUAUAUU G UAUCA	363	UGAUA UGAUGGCAUGCACUAUGCGCG AAUAUACGUC	890
4243	UGUAUCAUUU G AGUGA	364	UCACU UGAUGGCAUGCACUAUGCGCG AAAUGAUACA	891
4247	UCAUUUGAGU G AAUGU	365	ACAUU UGAUGGCAUGCACUAUGCGCG ACUCAAAUGA	892
4251	UUGAGUGAAU G UUCCC	366	GGGAA UGAUGGCAUGCACUAUGCGCG AUUCACUCAA	893
4285	CUAUUUAACU G AGUCA	367	UGACU UGAUGGCAUGCACUAUGCGCG AGUUAAAUAG	894
4295	GAGUCACACU G CAUAG	368	CUAUG UGAUGGCAUGCACUAUGCGCG AGUGUGACUC	895
4299	CACACUGCAU A GGAAU	369	AUUCC UGAUGGCAUGCACUAUGCGCG AUGCAGUGUG	896
4323	UAACUUUUAU A GGUUA	370	UAACC UGAUGGCAUGCACUAUGCGCG AUAAAAGUUA	897
4337	UAUCAAAACU G UUGUC	371	GACAA UGAUGGCAUGCACUAUGCGCG AGUUUUGAUA	898
4340	CAAAACUGUU G UCACC	372	GGUGA UGAUGGCAUGCACUAUGCGCG AACAGUUUUG	899
4349	UGUCACCAUU G CACAA	373	UUGUG UGAUGGCAUGCACUAUGCGCG AAUGGUGACA	900
4359	GCACAAUUUU G UCCUA	374	UAGGA UGAUGGCAUGCACUAUGCGCG AAAAUUGUGC	901
4367	UUGUCCUAAU A UAUAC	375	GUAUA UGAUGGCAUGCACUAUGCGCG AUUAGGACAA	902
4369	GUCCUAAUAU A UACAU	376	AUGUA UGAUGGCAUGCACUAUGCGCG AUAUUAGGAC	903
4371	CCUAAUAUAU A CAUAG	377	CUAUG UGAUGGCAUGCACUAUGCGCG AUAUAUUAGG	904
4375	AUAUAUACAU A GAAAC	378	GUUUC UGAUGGCAUGCACUAUGCGCG AUGUAUAUAU	905
4384	UAGAAACUUU G UGGGG	379	CCCCA UGAUGGCAUGCACUAUGCGCG AAAGUUUCUA	906
4393	UGUGGGGCAU G UUAAG	380	CUUAA UGAUGGCAUGCACUAUGCGCG AUGCCCCACA	907
4408	GUUACAGUUU G CACAA	381	UUGUG UGAUGGCAUGCACUAUGCGCG AAACUGUAAC	908
4427	CAUCUCAUUU G UAUUC	382	GAAUA UGAUGGCAUGCACUAUGCGCG AAAUGAGAUG	909
4437	GUAUUCCAUU G AUUUU	383	AAAAU UGAUGGCAUGCACUAUGCGCG AAUGGAAUAC	910
4480	AAAACAGUAU A UAUAA	384	UUAUA UGAUGGCAUGCACUAUGCGCG AUACUGUUUU	911
4482	AACAGUAUAU A UAACU	385	AGUUA UGAUGGCAUGCACUAUGCGCG AUAUACUGUU	912
4484	CAGUAUAUAU A ACUUU	386	AAAGU UGAUGGCAUGCACUAUGCGCG AUAUAUACUG	913
4527	AAAACUAUCU G AAGAU	387	AUCUU UGAUGGCAUGCACUAUGCGCG AGAUAGUUUU	914
4541	AUUUCCAUUU G UCAAA	388	UUUGA UGAUGGCAUGCACUAUGCGCG AAAUGGAAAU	915
4554	AAAAAGUAAU G AUUUC	389	GAAAU UGAUGGCAUGCACUAUGCGCG AUUACUUUUU	916
4562	AUGAUUUCUU G AUAAU	390	AUUAU UGAUGGCAUGCACUAUGCGCG AAGAAAUCAU	917
4565	AUUUCUUGAU A AUUGU	391	ACAAU UGAUGGCAUGCACUAUGCGCG AUCAAGAAAU	918
4569	CUUGAUAAUU G UGUAG	392	CUACA UGAUGGCAUGCACUAUGCGCG AAUUAUCAAG	919
4571	UGAUAAUUGU G UAGUG	393	CACUA UGAUGGCAUGCACUAUGCGCG ACAAUUAUCA	920
4576	AUUGUGUAGU G AAUGU	394	ACAUU UGAUGGCAUGCACUAUGCGCG ACUACACAAU	921
4580	UGUAGUGAAU G UUUUU	395	AAAAA UGAUGGCAUGCACUAUGCGCG AUUCACUACA	922
4606	CAGUUACCUU G AAAGC	396	GCUUU UGAUGGCAUGCACUAUGCGCG AAGGUAACUG	923
4613	CUUGAAAGCU G AAUUU	397	AAAUU UGAUGGCAUGCACUAUGCGCG AGCUUUCAAG	924
4621	CUGAAUUUAU A UUUAG	398	CUAAA UGAUGGCAUGCACUAUGCGCG AUAAAUUCAG	925
4635	AGUAACUUCU G UGUUA	399	UAACA UGAUGGCAUGCACUAUGCGCG AGAAGUUACU	926
4637	UAACUUCUGU G UUAAU	400	AUUAA UGAUGGCAUGCACUAUGCGCG ACAGAAGUUA	927
4643	CUGUGUUAAU A CUGGA	401	UCCAG UGAUGGCAUGCACUAUGCGCG AUUAACACAG	928
4650	AAUACUGGAU A GCAUG	402	CAUGC UGAUGGCAUGCACUAUGCGCG AUCCAGUAUU	929
4655	UGGAUAGCAU G AAUUC	403	GAAUU UGAUGGCAUGCACUAUGCGCG AUGCUAUCCA	930
4662	CAUGAAUUCU G CAUUG	404	CAAUG UGAUGGCAUGCACUAUGCGCG AGAAUUCAUG	931
4667	AUUCUGCAUU G AGAAA	405	UUUCU UGAUGGCAUGCACUAUGCGCG AAUGCAGAAU	932
4675	UUGAGAAACU G AAUAG	406	CUAUU UGAUGGCAUGCACUAUGCGCG AGUUUCUCAA	933
4679	GAAACUGAAU A GCUGU	407	ACAGC UGAUGGCAUGCACUAUGCGCG AUUCAGUUUC	934
4683	CUGAAUAGCU G UCAUA	408	UAUGA UGAUGGCAUGCACUAUGCGCG AGCUAUUCAG	935
4688	UAGCUGUCAU A AAAUG	409	CAUUU UGAUGGCAUGCACUAUGCGCG AUGACAGCUA	936
4693	GUCAUAAAAU G CUUUC	410	GAAAG UGAUGGCAUGCACUAUGCGCG AUUUUAUGAC	937
4715	AAAGAAAGAU A CUCAC	411	GUGAG UGAUGGCAUGCACUAUGCGCG AUCUUUCUUU	938
4723	AUACUCACAU G AGUUC	412	GAACU UGAUGGCAUGCACUAUGCGCG AUGUGAGUAU	939
4731	AUGAGUUCUU G AAGAA	413	UUCUU UGAUGGCAUGCACUAUGCGCG AAGAACUCAU	940
4738	CUUGAAGAAU A GUCAU	414	AUGAC UGAUGGCAUGCACUAUGCGCG AUUCUUCAAG	941
4744	GAAUAGUCAU A ACUAG	415	CUAGU UGAUGGCAUGCACUAUGCGCG AUGACUAUUC	942
4760	AUUAAGAUCU G UGUUU	416	AAACA UGAUGGCAUGCACUAUGCGCG AGAUCUUAAU	943
4762	UAAGAUCUGU G UUUUA	417	UAAAA UGAUGGCAUGCACUAUGCGCG ACAGAUCUUA	944
4775	UUAGUUUAAU A GUUUG	418	CAAAC UGAUGGCAUGCACUAUGCGCG AUUAAACUAA	945
4780	UUAAUAGUUU G AAGUG	419	CACUU UGAUGGCAUGCACUAUGCGCG AAACUAUUAA	946
4785	AGUUUGAAGU G CCUGU	420	ACAGG UGAUGGCAUGCACUAUGCGCG ACUUCAAACU	947
4789	UGAAGUGCCU G UUUGG	421	CCAAA UGAUGGCAUGCACUAUGCGCG AGGCACUUCA	948
4798	UGUUUGGGAU A AUGAU	422	AUCAU UGAUGGCAUGCACUAUGCGCG AUCCCAAACA	949
4801	UUGGGAUAAU G AUAGG	423	CCUAU UGAUGGCAUGCACUAUGCGCG AUUAUCCCAA	950
4804	GGAUAAUGAU A GGUAA	424	UUACC UGAUGGCAUGCACUAUGCGCG AUCAUUAUCC	951
4817	UAAUUUAGAU G AAUUU	425	AAAUU UGAUGGCAUGCACUAUGCGCG AUCUAAAUUA	952
4843	AAAGUUAUCU G CAGUU	426	AACUG UGAUGGCAUGCACUAUGCGCG AGAUAACUUU	953
4851	CUGCAGUUAU G UUGAG	427	CUCAA UGAUGGCAUGCACUAUGCGCG AUAACUGCAG	954
4854	CAGUUAUGUU G AGGGC	428	GCCCU UGAUGGCAUGCACUAUGCGCG AACAUAACUG	955
4904	GGGUUACAGU G UUUUA	429	UAAAA UGAUGGCAUGCACUAUGCGCG ACUGUAACCC	956
4913	UGUUUUAUCC G AAAGU	430	ACUUU UGAUGGCAUGCACUAUGCGCG GGAUAAAACA	957
4932	CAAUUCCACU G UCUUG	431	CAAGA UGAUGGCAUGCACUAUGCGCG AGUGGAAUUG	958
4937	CCACUGUCUU G UGUUU	432	AAACA UGAUGGCAUGCACUAUGCGCG AAGACAGUGG	959
4939	ACUGUCUUGU G UUUUC	433	GAAAA UGAUGGCAUGCACUAUGCGCG ACAAGACAGU	960
4947	GUGUUUUCAU G UUGAA	434	UUCAA UGAUGGCAUGCACUAUGCGCG AUGAAAACAC	961
4950	UUUUCAUGUU G AAAAU	435	AUUUU UGAUGGCAUGCACUAUGCGCG AACAUGAAAA	962
4956	UGUUGAAAAU A CUUUU	436	AAAAG UGAUGGCAUGCACUAUGCGCG AUUUUCAACA	963
4962	AAAUACUUUU G CAUUU	437	AAAUG UGAUGGCAUGCACUAUGCGCG AAAAGUAUUU	964
4975	UUUUUCCUUU G AGUGC	438	GCACU UGAUGGCAUGCACUAUGCGCG AAAGGAAAAA	965
4979	UCCUUUGAGU G CCAAU	439	AUUGG UGAUGGCAUGCACUAUGCGCG ACUCAAAGGA	966
5009	AUUUCUUAAU G UAACA	440	UGUUA UGAUGGCAUGCACUAUGCGCG AUUAAGAAAU	967
5016	AAUGUAACAU G UUUAC	441	GUAAA UGAUGGCAUGCACUAUGCGCG AUGUUACAUU	968
5029	UACCUGGCCU G UCUUU	442	AAAGA UGAUGGCAUGCACUAUGCGCG AGGCCAGGUA	969
5046	AACUAUUUUU G UAUAG	443	CUAUA UGAUGGCAUGCACUAUGCGCG AAAAAUAGUU	970
5050	AUUUUUGUAU A GUGUA	444	UACAC UGAUGGCAUGCACUAUGCGCG AUACAAAAAU	971
5053	UUUGUAUAGU G UAAAC	445	GUUUA UGAUGGCAUGCACUAUGCGCG ACUAUACAAA	972
5060	AGUGUAAACU G AAACA	446	UGUUU UGAUGGCAUGCACUAUGCGCG AGUUUACACU	973
5067	ACUGAAACAU G CACAU	447	AUGUG UGAUGGCAUGCACUAUGCGCG AUGUUUCAGU	974
5076	UGCACAUUUU G UACAU	448	AUGUA UGAUGGCAUGCACUAUGCGCG AAAAUGUGCA	975
5083	UUUGUACAUU G UGCUU	449	AAGCA UGAUGGCAUGCACUAUGCGCG AAUGUACAAA	976
5085	UGUACAUUGU G CUUUC	450	GAAAG UGAUGGCAUGCACUAUGCGCG ACAAUGUACA	977
5095	GCUUUCUUUU G UGGGU	451	ACCCA UGAUGGCAUGCACUAUGCGCG AAAAGAAAGC	978
5104	UGUGGGUCAU A UGCAG	452	CUGCA UGAUGGCAUGCACUAUGCGCG AUGACCCACA	979
5106	UGGGUCAUAU G CAGUG	453	CACUG UGAUGGCAUGCACUAUGCGCG AUAUGACCCA	980
5111	CAUAUGCAGU G UGAUC	454	GAUCA UGAUGGCAUGCACUAUGCGCG ACUGCAUAUG	981
5113	UAUGCAGUGU G AUCCA	455	UGGAU UGAUGGCAUGCACUAUGCGCG ACACUGCAUA	982
5122	UGAUCCAGUU G UUUUC	456	GAAAA UGAUGGCAUGCACUAUGCGCG AACUGGAUCA	983
5140	UCAUUUGGUU G CGCUG	457	CAGCG UGAUGGCAUGCACUAUGCGCG AACCAAAUGA	984
5142	AUUUGGUUGC G CUGAC	458	GUCAG UGAUGGCAUGCACUAUGCGCG GCAACCAAAU	985
5145	UGGUUGCGCU G ACCUA	459	UAGGU UGAUGGCAUGCACUAUGCGCG AGCGCAACCA	986
5156	ACCUAGGAAU G UUGGU	460	ACCAA UGAUGGCAUGCACUAUGCGCG AUUCCUAGGU	987
5165	UGUUGGUCAU A UCAAA	461	UUUGA UGAUGGCAUGCACUAUGCGCG AUGACCAACA	988
5181	CAUUAAAAAU G ACCAC	462	GUGGU UGAUGGCAUGCACUAUGCGCG AUUUUUAAUG	989
5196	CUCUUUUAAU G AAAUU	463	AAUUU UGAUGGCAUGCACUAUGCGCG AUUAAAAGAG	990
5213	ACUUUUAAAU G UUUAU	464	AUAAA UGAUGGCAUGCACUAUGCGCG AUUUAAAAGU	991
5219	AAAUGUUUAU A GGAGU	465	ACUCC UGAUGGCAUGCACUAUGCGCG AUAAACAUUU	992
5227	AUAGGAGUAU G UGCUG	466	CAGCA UGAUGGCAUGCACUAUGCGCG AUACUCCUAU	993
5229	AGGAGUAUGU G CUGUG	467	CACAG UGAUGGCAUGCACUAUGCGCG ACAUACUCCU	994
5232	AGUAUGUGCU G UGAAG	468	CUUCA UGAUGGCAUGCACUAUGCGCG AGCACAUACU	995
5234	UAUGUGCUGU G AAGUG	469	CACUU UGAUGGCAUGCACUAUGCGCG ACAGCACAUA	996
5239	GCUGUGAAGU G AUCUA	470	UAGAU UGAUGGCAUGCACUAUGCGCG ACUUCACAGC	997
5251	UCUAAAAUUU G UAAUA	471	UAUUA UGAUGGCAUGCACUAUGCGCG AAAUUUUAGA	998
5256	AAUUUGUAAU A UUUUU	472	AAAAA UGAUGGCAUGCACUAUGCGCG AUUACAAAUU	999
5262	UAAUAUUUUU G UCAUG	473	CAUGA UGAUGGCAUGCACUAUGCGCG AAAAAUAUUA	1000
5267	UUUUUGUCAU G AACUG	474	CAGUU UGAUGGCAUGCACUAUGCGCG AUGACAAAAA	1001
5272	GUCAUGAACU G UACUA	475	UAGUA UGAUGGCAUGCACUAUGCGCG AGUUCAUGAC	1002
5290	CCUAAUUAUU G UAAUG	476	CAUUA UGAUGGCAUGCACUAUGCGCG AAUAAUUAGG	1003
5295	UUAUUGUAAU G UAAUA	477	UAUUA UGAUGGCAUGCACUAUGCGCG AUUACAAUAA	1004
5300	GUAAUGUAAU A AAAAU	478	AUUUU UGAUGGCAUGCACUAUGCGCG AUUACAUUAC	1005
5306	UAAUAAAAAU A GUUAC	479	GUAAC UGAUGGCAUGCACUAUGCGCG AUUUUUAUUA	1006
5315	UAGUUACAGU G ACUAU	480	AUAGU UGAUGGCAUGCACUAUGCGCG ACUGUAACUA	1007
5321	CAGUGACUAU G AGUGU	481	ACACU UGAUGGCAUGCACUAUGCGCG AUAGUCACUG	1008
5325	GACUAUGAGU G UGUAU	482	AUACA UGAUGGCAUGCACUAUGCGCG ACUCAUAGUC	1009
5327	CUAUGAGUGU G UAUUU	483	AAAUA UGAUGGCAUGCACUAUGCGCG ACACUCAUAG	1010
5339	AUUUAUUCAU G CAAAU	484	AUUUG UGAUGGCAUGCACUAUGCGCG AUGAAUAAAU	1011
5347	AUGCAAAUUU G AACUG	485	CAGUU UGAUGGCAUGCACUAUGCGCG AAAUUUGCAU	1012
5352	AAUUUGAACU G UUUGC	486	GCAAA UGAUGGCAUGCACUAUGCGCG AGUUCAAAUU	1013
5356	UGAACUGUUU G CCCCG	487	CGGGG UGAUGGCAUGCACUAUGCGCG AAACAGUUCA	1014
5361	UGUUUGCCCC G AAAUG	488	CAUUU UGAUGGCAUGCACUAUGCQCG GGGGCAAACA	1015
5366	GCCCCGAAAU G GAUAU	489	AUAUC UGAUGGCAUGCACUAUGCGCG AUUUCGGGGC	1016
5370	CGAAAUGGAU A UGGAU	490	AUCCA UGAUGGCAUGCACUAUGCGCG AUCCAUUUCG	1017
5372	AAAUGGAUAU G GAUAC	491	GUAUC UGAUGGCAUGCACUAUGCGCG AUAUCCAUUU	1018
5376	GGAUAUGGAU A CUUUA	492	UAAAG UGAUGGCAUGCACUAUGCGCG AUCCAUAUCC	1019
5383	GAUACUUUAU A AGCCA	493	UGGCU UGAUGGCAUGCACUAUGCGCG AUAAAGUAUC	1020
5390	UAUAAGCCAU A GACAC	494	GUGUC UGAUGGCAUGCACUAUGCGCG AUGGCUUAUA	1021
5399	UAGACACUAU A GUAUA	495	UAUAC UGAUGGCAUGCACUAUGCGCG AUAGUGUCUA	1022
5404	ACUAUAGUAU A CCAGU	496	ACUGG UGAUGGCAUGCACUAUGCGCG AUACUAUAGU	1023
5410	GUAUACCAGU G AAUCU	497	AGAUU UGAUGGCAUGCACUAUGCGCG ACUGGUAUAC	1024
5421	AAUCUUUUAU G CAGCU	498	AGCUG UGAUGGCAUGCACUAUGCGCG AUAAAAGAUU	1025
5428	UAUGCAGCUU G UUAGA	499	UCUAA UGAUGGCAUGCACUAUGCGCG AAGCUGCAUA	1026
5459	UCUAAAAGGU G CUGUG	500	CACAG UGAUGGCAUGCACUAUGCGCG ACCUUUUAGA	1027
5462	AAAAGGUGCU G UGGAU	501	AUCCA UGAUGGCAUGCACUAUGCGCG AGCACCUUUU	1028
5468	UGCUGUGGAU A UUAUG	502	CAUAA UGAUGGCAUGCACUAUGCGCG AUCCACAGCA	1029
5473	UGGAUAUUAU G UAAAG	503	CUUUA UGAUGGCAUGCACUAUGCGCG AUAAUAUCCA	1030
5483	GUAAAGGCGU G UUUGC	504	GCAAA UGAUGGCAUGCACUAUGCGCG ACGCCUUUAC	1031
5487	AGGCGUGUUU G CUUAA	505	UUAAG UGAUGGCAUGCACUAUGCGCG AAACACGCCU	1032
5505	AAUUUUCCAU A UUUAG	506	CUAAA UGAUGGCAUGCACUAUGCGCG AUGGAAAAUU	1033
5519	AGAAGUAGAU G CAAAA	507	UUUUG UGAUGGCAUGCACUAUGCGCG AUCUACUUCU	1034
5532	AAACAAAUCU G CCUUU	508	AAAGG UGAUGGCAUGCACUAUGCGCG AGAUUUGUUU	1035
5540	CUGCCUUUAU G ACAAA	509	UUUGU UGAUGGCAUGCACUAUGCGCG AUAAAGGCAG	1036
5551	ACAAAAAAAU A GGAUA	510	UAUCC UGAUGGCAUGCACUAUGCGCG AUUUUUUUGU	1037
5556	AAAAUAGGAU A ACAUU	511	AAUGU UGAUGGCAUGCACUAUGCGCG AUCCUAUUUU	1038
5586	UUUUAUCAAU A AGGUA	512	UACCU UGAUGGCAUGCACUAUGCGCG AUUGAUAAAA	1039
5595	UAAGGUAAUU G AUACA	513	UGUAU UGAUGGCAUGCACUAUGCGCG AAUUACCUUA	1040
5598	GGUAAUUGAU A CACAA	514	UUGUG UGAUGGCAUGCACUAUGCGCG AUCAAUUACC	1041
5609	CACAACAGGU G ACUUG	515	CAAGU UGAUGGCAUGCACUAUGCGCG ACCUGUUGUG	1042
5650	CAACAUUAAU A AUGGA	516	UCCAU UGAUGGCAUGCACUAUGCGCG AUUAAUGUUG	1043
5653	CAUUAAUAAU G GAAAU	517	AUUUC UGAUGGCAUGCACUAUGCGCG AUUAUUAAUG	1044
5659	UAAUGGAAAU A AUUGA	518	UCAAU UGAUGGCAUGCACUAUGCGCG AUUUCCAUUA	1045
5663	GGAAAUAAUU G AAUAG	519	CUAUU UGAUGGCAUGCACUAUGCGCG AAUUAUUUCC	1046
5667	AUAAUUGAAU A GUUAG	520	CUAAC UGAUGGCAUGCACUAUGCGCG AUUCAAUUAU	1047
5677	AGUUAGUUAU G UAUGU	521	ACAUA UGAUGGCAUGCACUAUGCGCG AUAACUAACU	1048
5681	AGUUAUGUAU G UUAAU	522	AUUAA UGAUGGCAUGCACUAUGCGCG AUACAUAACU	1049
5687	GUAUGUUAAU G CCAGU	523	ACUGG UGAUGGCAUGCACUAUGCGCG AUUAACAUAC	1050
5725	CAGAAGUAAU G ACUCC	524	GGAGU UGAUGGCAUGCACUAUGCGCG AUUACUUCUG	1051
5733	AUGACUCCAU A CAUAU	525	AUAUG UGAUGGCAUGCACUAUGCGCG AUGGAGUCAU	1052
5737	CUCCAUACAU A UUAUU	526	AAUAA UGAUGGCAUGCACUAUGCGCG AUGUAUGGAG	1053
5752	UUAUUUCUAU A ACUAC	527	GUAGU UGAUGGCAUGCACUAUGCGCG AUAGAAAUAA	1054
Input Sequence = KRAS2 Cut Site = AUR/, YG/M or UG/U.
Stem Length = 5/10. Core Sequence = UGAUGGCAUGCACUAUGCGCG
Seq1 = KRAS2 ( Homo sapiens v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS2) mRNA.; 5775 bp)

TABLE III — with next nucleotide specified. Reaction conditions as in text, na = no activity detectable, single turnover kinetics.

Cleavable Triplet	k cat (min −1 )
A 14.2 U 14.1 G 15 /A 1.1	0.91
A 14.2 U 14.1 A 15 /A 1.1	0.34
A 14.2 U 14.1 U 15 /A 1.1	0.007
A 14.2 A 14.1 G 15 /A 1.1	0.57
A 14.2 U 14.1 G 15 /U 1.1	0.35
A 14.2 U 14.1 G 15 /G 1.1	0.66
/ = site of cleavage
Numbering convention as shown in FIG. 8

TABLE IV — Sequence Specificity and Rate Constants for Stabilized Ribozymes Cleavage

Site				k rel to
Sequence	RPI #	Corresponding Ribozyme	Seq. ID Nos	WT
WT =	13159	5′-aac guu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1055	1
UG/A
UG/C	12768	5′-aac ggu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1056	0.97
CG/A	13161	5′-aac guu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1057	0.76
AG/A	12763	5′-aac guu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1058	0.70
UG/U	12764	5′-aac gau GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1059	0.35
CG/U	12766	5′-aac gau GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1060	0.12
CG/C	12770	5′-aac ggu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1061	0.1
AG/C	12771	5′-aac ggu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1062	0.07
AG/U	12767	5′-aac gau GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1063	0.06
CG/G	12774	5′-aac gcu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1064	0.06
UG/G	12772	5′-aac gcu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1065	0.04
GG/A	13160	5′-aac guu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1066	0.02
GG/C	12769	5′-aac ggu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1067	0.01
AG/G	12775	5′-aac gcu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1068	0.008
GG/U	12765	5′-aac gau GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1069	0.007
GG/G	12773	5′-aac gcu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1070	0.002
Lower case = 2′-O-Methyl
Upper case = Ribo
s = phosphorothioate
/= site of cleavage
WT U 14.1 G 15 /A 1.1 (FIG. 8) K obs = 0.266 min −1

TABLE V — Human K-ras Ribozyme Sequences

	Nt.			Seq. ID
RPI #	Position	Alias	Ribozyme Sequence	No.
12779	63	krasM-63 GCl.Rz-5/10 stab1	a s g s cug uGAU s g gcauGcacuaugc gcg aucgucaagg B	1071
12780	95	krasM-95 GCl.Rz-5/10 stab1	g s a s uca uGAU s g gcauGcacuaugc gcg auucguccac B	1072
12781	142	krasM-142 GCl.Rz-5/10 stab1	u s u s cuc uGAU s g gcauGcacuaugc gcg aucaauuacu B	1073
12782	163	krasM-163 GCl.Rz-5/10 stab1	g s a s gaa uGAU s g gcauGcacuaugc gcg auccaagaga B	1074
12783	201	krasM-201 GCl.Rz-5/10 stab1	u s c s ccu uGAU s g gcauGcacuaugc gcg auugcacugu B	1075
12784	216	krasM-216 GCl.Rz-5/10 stab1	g s u s ccu uGAU s g gcauGcacuaugc gcg auguacuggu B	1076
12785	256	krasM-256 GCl.Rz-5/10 stab1	a s g s uau uGAU s g gcauGcacuaugc gcg auuuauggca B	1077
12786	325	krasM-325 GCl.Rz-5/10 stab1	a s g s gua uGAU s g gcauGcacuaugc gcg aucuucagag B	1078
12787	333	krasM-333 GCl.Rz-5/10 stab1	a s g s gac uGAU s g gcauGcacuaugc gcg auagguacau B	1079
12788	353	krasM-353 GCl.Rz-5/10 stab1	a s a s uca uGAU s g gcauGcacuaugc gcg auuuauuucc B	1080
12789	412	krasM-412 GCl.Rz-5/10 stab1	a s a s uuc uGAU s g gcauGcacuaugc gcg auaacuucuu B	1081
12790	460	krasM-460 GCl.Rz-5/10 stab1	g s g s cau uGAU s g gcauGcacuaugc gcg aucaacaccc B	1082
12791	463	krasM-463 GCl.Rz-5/10 stab1	g s a s agg uGAU s g gcauGcacuaugc gcg aucaucaaca B	1083
12792	472	krasM-472 GCl.Rz-5/10 stab1	u s a s aug uGAU s g gcauGcacuaugc gcg auagaaggca B	1084
12793	520	krasM-520 GCl.Rz-5/10 stab1	u s u s uac uGAU s g gcauGcacuaugc gcg aucuuugcuc B	1085
12794	706	krasM-706 GCl.Rz-5/10 stab1	a s u s aag uGAU s g gcauGcacuaugc gcg auuuaaggua B	1086
12795	787	krasM-787 GCl.Rz-5/10 stab1	a s c s agg uGAU s g gcauGcacuaugc gcg auugcuaguu B	1087
12796	843	krasM-843 GCl.Rz-5/10 stab1	a s a s cug uGAU s g gcauGcacuaugc gcg augcaccaaa B	1088
12797	882	krasM-882 GCl.Rz-5/10 stab1	a s c s caa uGAU s g gcauGcacuaugc gcg auucacacuu B	1089
12798	903	krasM-903 GCl.Rz-5/10 stab1	a s g s cuu uGAU s g gcauGcacuaugc gcg auuaauuugu B	1090
12799	951	krasM-951 GCl.Rz-5/10 stab1	u s a s auc uGAU s g gcauGcacuaugc gcg auuuauguga B	1091
12800	1022	krasM-1022 GCl.Rz-5/10 stab1	a s a s gcc uGAU s g gcauGcacuaugc gcg auaaauuugu B	1092
12801	1034	krasM-1034 GCl.Rz-5/10 stab1	a s u s cau uGAU s g gcauGcacuaugc gcg aucaggaagc B	1093
12802	1037	krasM-1037 GCl.Rz-5/10 stab1	a s g s aau uGAU s g gcauGcacuaugc gcg aucaucagga B	1094
12803	1079	krasM-1079 GCl.Rz-5/10 stab1	a s c s auu uGAU s g gcauGcacuaugc gcg aucagggaug B	1095
12804	1083	krasM-1083 GCl.Rz-5/10 stab1	c s u s uua uGAU s g gcauGcacuaugc gcg auucaucagg B	1096
12805	1206	krasM-1206 GCl.Rz-5/10 stab1	g s u s uuc uGAU s g gcauGcacuaugc gcg auugccuugu B	1097
12806	1218	krasM-1218 GCl.Rz-5/10 stab1	g s g s ccu uGAU s g gcauGcacuaugc gcg auaauaguuu B	1098
12807	1267	krasM-1267 GCl.Rz-5/10 stab1	a s a s agc uGAU s g gcauGcacuaugc gcg auuaggaguc B	1099
12808	1301	krasM-1301 GCl.Rz-5/10 stab1	a s a s ucc uGAU s g gcauGcacuaugc gcg auucauacug B	1100
12809	1312	krasM-1312 GCl.Rz-5/10 stab1	g s u s ugc uGAU s g gcauGcacuaugc gcg auaauaaucc B	1101
12810	1529	krasM-1529 GCl.Rz-5/10 stab1	u s a s agc uGAU s g gcauGcacuaugc gcg auaacuggcc B	1102
12811	1594	krasM-1594 GCl.Rz-5/10 stab1	c s u s cuc uGAU s g gcauGcacuaugc gcg augaaagcuc B	1103
12812	1611	krasM-1611 GCl.Rz-5/10 stab1	c s a s guc uGAU s g gcauGcacuaugc gcg augcugugaa B	1104
12813	1650	krasM-1650 GCl.Rz-5/10 stab1	c s a s aug uGAU s g gcauGcacuaugc gcg aucguacaac B	1105
12814	1694	krasM-1694 GCl.Rz-5/10 stab1	u s g s agc uGAU s g gcauGcacuaugc gcg auccaaacug B	1106
12815	1867	krasM-1867 GCl.Rz-5/10 stab1	c s a s cuu uGAU s g gcauGcacuaugc gcg auuguuuaaa B	1107
12816	1936	krasM-1936 GCl.Rz-5/10 stab1	g s u s guu uGAU s g gcauGcacuaugc gcg augcaauguu B	1108
12817	1960	krasM-1960 GCl.Rz-5/10 stab1	u s u s aaa uGAU s g gcauGcacuaugc gcq auggaucaga B	1109
12818	2046	krasM-2046 GCl.Rz-5/10 stab1	c s a s ugc uGAU s g gcauGcacuaugc gcg aucucacuuc B	1110
12819	2051	krasM-2051 GCl.Rz-5/10 stab1	c s u s cac uGAU s g gcauGcacuaugc gcg augccaucuc B	1111
12820	2103	krasM-2103 GCl.Rz-5/10 stab1	a s c s acc uGAU s g gcauGcacuaugc gcg aucuagaacc B	1112
12821	2158	krasM-2158 GCl.Rz-5/10 stab1	u s u s uaa uGAU s g gcauGcacuaugc gcg augaagaaau B	1113
12822	2214	krasM-2214 GCl.Rz-5/10 stab1	u s g s gaa uGAU s g gcauGcacuaugc gcg auaaaucaca B	1114
12823	2227	krasM-2227 GCl.Rz-5/10 stab1	a s u s ccu uGAU s g gcauGcacuaugc gcg auguaaaugg B	1115
12824	2422	krasM-2422 GCl.Rz-5/10 stab1	a s a s cug uGAU s g gcauGcacuaugc gcg aucaagucau B	1116
12825	2454	krasM-2454 GCl.Rz-5/10 stab1	a s a s ucu uGAU s g gcauGcacuaugc gcg augguuaggg B	1117
12826	2476	krasM-2476 GCl.Rz-5/10 stab1	g s g s aga uGAU s g gcauGcacuaugc gcg auccacagca B	1118
12827	2484	krasM-2484 GCl.Rz-5/10 stab1	a s a s cuu uGAU s g gcauGcacuaugc gcg auggagauau B	1119
12828	2514	krasM-2514 GCl.Rz-5/10 stab1	u s a s ggg uGAU s g gcauGcacuaugc gcg auuucugaug B	1120
12829	2564	krasM-2564 GCl Rz-5/10 stab1	c s c s cuu uGAU s g gcauGcacuaugc gcg augguaucug B	1121
12830	2607	krasM-2607 GCl.Rz-5/10 stab1	c s a s aag uGAU s g gcauGcacuaugc gcg aucagccacc B	1122
12831	2669	krasM-2669 GCl.Rz-5/10 stab1	c s u s auu uGAU s g gcauGcacuaugc gcg auaccagggu B	1123
12832	2806	krasM-2806 GCl.Rz-5/10 stab1	c s a s uug uGAU s g gcauGcacuaugc gcg augaagauuu B	1124
12833	2830	krasM-2830 GCl.Rz-5/10 stab1	a s g s cuu uGAU s g gcauGcacuaugc gcg augaauuaaa B	1125
12834	2888	krasM-2888 GCl.Rz-5/10 stab1	c s a s cug uGAU s g gcauGcacuaugc gcg auuccagccu B	1126
12835	3095	krasM-3095 GCl.Rz-5/10 stab1	a s g s guu uGAU s g gcauGcacuaugc gcg augaggccaa B	1127
12836	3130	krasM-3130 GCl.Rz-5/10 stab1	a s u s aaa uGAU s g gcauGcacuaugc gcg auuugcugaa B	1128
12837	3152	krasM-3152 GCl.Rz-5/10 stab1	a s c s ugg uGAU s g gcauGcacuaugc gcg aucugguagg B	1129
12838	3180	krasM-3180 GCl.Rz-5/10 stab1	u s a s cca uGAU s g gcauGcacuaugc gcg auacccagug B	1130
12839	3182	krasM-3182 GCl.Rz-5/10 stab1	g s a s uac uGAU s g gcauGcacuaugc gcg auauacccag B	1131
12840	3204	krasM-3204 GCl.Rz-5/10 stab1	g s g s gau uGAU s g gcauGcacuaugc gcg augucucuug B	1132
12841	3264	krasM-3264 GCl.Rz-5/10 stab1	g s g s ucg uGAU s g gcauGcacuaugc gcg auaccaaagg B	1133
12842	3277	krasM-3277 GCl.Rz-5/10 stab1	c s g s ugu uGAU s g gcauGcacuaugc gcg aucucugggu B	1134
12843	3285	krasM-3285 GCl.Rz-5/10 stab1	a s u s acg uGAU s g gcauGcacuaugc gcg aucguguuau B	1135
12844	3335	krasM-3335 GCl.Rz-5/10 stab1	a s c s aau uGAU s g gcauGcacuaugc gcg auagagcugg B	1136
12845	3412	krasM-3412 GCl.Rz-5/10 stab1	a s a s guu uGAU s g gcauGcacuaugc gcg auuccuuuaa B	1137
12846	3444	krasM-3444 GCl.Rz-5/10 stab1	a s c s agu uGAU s g gcauGcacuaugc gcg augccaaaua B	1138
12847	3514	krasM-3514 GCl.Rz-5/10 stab1	u s u s aca uGAU s g gcauGcacuaugc gcg auuuggguca B	1139
12848	3521	krasM-3521 GCl.Rz-5/10 stab1	u s g s gaa uGAU s g gcauGcacuaugc gcg auuacacauu B	1140
12849	3540	krasM-3540 GCl.Rz-5/10 stab1	u s u s acu uGAU s g gcauGcacuaugc gcg augcagagaa B	1141
12850	3589	krasM-3589 GCl.Rz-5/10 stab1	c s u s guu uGAU s g gcauGcacuaugc gcg auuuguaccc B	1142
12851	3662	krasM-3662 GCl.Rz-5/10 stab1	u s u s uca uGAU s g gcauGcacuaugc gcg auagcaauuc B	1143
12852	3746	krasM-3746 GCl.Rz-5/10 stab1	a s u s ggc uGAU s g gcauGcacuaugc gcg auuucuuucu B	1144
12853	3752	krasM-3752 GCl.Rz-5/10 stab1	u s g s aag uGAU s g gcauGcacuaugc gcg auggccauuu B	1145
12854	3813	krasM-3813 GCl.Rz-5/10 stab1	a s u s gcc uGAU s g gcauGcacuaugc gcg aucuacauca B	1146
12855	3849	krasM-3849 GCl.Rz-5/10 stab1	g s u s uca uGAU s g gcauGcacuaugc gcg auaaagguaa B	1147
12856	3862	krasM-3862 GCl.Rz-5/10 stab1	u s a s aac uGAU s g gcauGcacuaugc gcg auucaaaguu B	1148
12857	4012	krasM-4012 GCl.Rz-5/10 stab1	a s c s aaa uGAU s g gcauGcacuaugc gcg auguuaaugc B	1149
12858	4026	krasM-4026 GCl.Rz-5/10 stab1	u s g s cua uGAU s g gcauGcacuaugc gcg auucuuccac B	1150
12859	4028	krasM-4028 GCl.Rz-5/10 stab1	u s c s ugc uGAU s g gcauGcacuaugc gcg auauucuucc B	1151
12860	4039	krasM-4039 GCl.Rz-5/10 stab1	u s a s caa uGAU s g gcauGcacuaugc gcg auacgucugc B	1152
12861	4059	krasM-4059 GCl.Rz-5/10 stab1	g s g s gaa uGAU s g gcauGcacuaugc gcg auucacucaa B	1153
12862	4107	krasM-4107 GCl.Rz-5/10 stab1	a s u s ucc uGAU s g gcauGcacuaugc gcg augcagugug B	1154
12863	4458	krasM-4458 GCl.Rz-5/10 stab1	c s a s ugc uGAU s g gcauGcacuaugc gcg auccaguauu B	1155
12864	4463	krasM-4463 GCl.Rz-5/10 stab1	g s a s auu uGAU s g gcauGcacuaugc gcg augcuaucca B	1156
12865	4487	krasM-4487 GCl.Rz-5/10 stab1	a s c s agc uGAU s g gcauGcacuaugc gcg auucaguuuc B	1157
12866	4606	krasM-4606 GCl.Rz-5/10 stab1	a s u s cau uGAU s g gcauGcacuaugc gcg aucccaaaca B	1158
12867	4609	krasM-4609 GCl.Rz-5/10 stab1	c s c s uau uGAU s g gcauGcacuaugc gcg auuaucccaa B	1159
12868	4659	krasM-4659 GCl.Rz-5/10 stab1	c s u s caa uGAU s g gcauGcacuaugc gcg auaacugcag B	1160
12869	4875	krasM-4875 GCl.Rz-5/10 stab1	a s u s gug uGAU s g gcauGcacuaugc gcg auguuucagu B	1161
12870	4912	krasM-4912 GCl.Rz-5/10 stab1	c s u s gca uGAU s g gcauGcacuaugc gcg augacccaca B	1162
12871	4914	krasM-4914 GCl.Rz-5/10 stab1	c s a s cug uGAU s g gcauGcacuaugc gcg auaugaccca B	1163
12872	4964	krasM-4964 GCl.Rz-5/10 stab1	a s c s caa uGAU s g gcauGcacuaugc gcg auuccuaggu B	1164
12873	4973	krasM-4973 GCl.Rz-5/10 stab1	u s u s uga uGAU s g gcauGcacuaugc gcg augaccaaca B	1165
12874	5035	krasM-5035 GCl.Rz-5/10 stab1	c s a s gca uGAU s g gcauGcacuaugc gcg auacuccuau B	1166
Lower Case = 2′-O-methyl
Upper Case = Ribo
s = phosphorothioate linkage
B = inverted deoxyabasic
1208
1	16	RNA	Homo sapiens

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50 claims

Classifications

12 codes

IPC · International Patent Classification

Section A — Human necessities

A61K38/00

Section C — Chemistry; metallurgy

C12N5/02
C12N15/113

USPC · US Patent Classification

435/375435/6435/91.31536/23.1536/24.5435/91.1536/23.2435/320.1435/325

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Sean McGarry

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