Antibodies to peptides that target GIT receptors and related methods

This Application claims the benefits of a Provisional Application No. 60/109,036 filed Nov. 19, 1998.

The present invention relates to antibodies to random peptides capable of targeting or specifically binding to gastrointestinal tract (GIT) transport receptors. In particular, this invention relates to methods of using these antibodies as well as specific antibody preparations directed to particular GIT random peptide targeting agents.

Antibodies can be produced by using an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library.

Various procedures known in the art may be useful for the production of polyclonal antibodies to an immunogen. For the production of antibody, various host animals, such as rabbits, mice, rats, fowl etc. can be immunized by injection with the immunogen. Various adjuvants may be used to increase the immunological response, depending on the host species, such as Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.

As disclosed and claimed in WO 98/51325, which reference is hereby incorporated by reference in its entirety, we have identified random peptides and their fragments, motifs, derivatives, analogs or peptidomimetics thereof which are capable of specific binding to GIT transport receptors such as the D2H, hSI, HPT1 and hPEPT1 receptors (hereinafter referred to as “GIT targeting agents”). These GIT targeting agents are capable of facilitating transport of an active agent through a human or animal gastro-intestinal tissue and have use, for example, in facilitating transport of active agents from the lumenal side of the GIT into the portal, hepatic or systemic blood system and/or in targeting active agents to the GIT. Thus, for example, by binding (covalently or noncovalently) the GIT targeting agent to an orally administered active agent, the active agent can be targeted to specific receptor sites or transport pathways which are known to operate in the human gastrointestinal tract, thus facilitating its absorption into the systemic system. Preferably, the active agent is a drug or a drug-containing nano- or microparticle. Preferably, the tissue through which transport is facilitated is of the duodenum, jejunum, ileum, ascending colon, transverse colon, descending colon, or pelvic colon. The tissue is most preferably epithelial cells lining the lumenal side of the GIT.

The GIT targeting agents are bound to a material comprising an active agent. Such compositions have use in targeting the active agent to the GIT and/or in facilitating transfer through the lumen of the GIT into the systemic circulation. Where the active agent is an imaging agent, such compositions can be administered in vivo to image the GIT (or particular transport receptors thereof). Other active agents include but are not limited to: any drug or antigen or any drug- or antigen-loaded or drug- or antigen-encapsulated nanoparticle, microparticle, liposome, or micellar formulation capable of eliciting a biological response in a human or animal. Examples of drug- or antigen-loaded or drug- or antigen-encapsulated formulations include those in which the active agent is encapsulated or loaded into nano- or microparticles, such as biodegradable nano- or microparticles, and which have GIT targeting agents adsorbed, coated or covalently bound, such as directly linked or linked via a linking moiety, onto the surface of the nano- or microparticle. Additionally, the GIT targeting agent can form the nano- or microparticle itself or the GIT targeting agent can be covalently attached to the polymer or polymers used in the production of the biodegradable nano- or microparticles or drug-loaded or drug-encapsulated nano- or microparticles or the peptide can be directly conjugated to the active agent.

The GIT targeting agent bound to the active agent can be employed in methods of treatment (and prophylaxis) by administration to a subject of an effective amount of targeting agent/active agent. Any disease or disorder of interest amenable to therapy or prophylaxis by providing a drug in vivo systemically or by targeting a drug in vivo to the GIT (by linkage to a GIT targeting agent) can be treated or prevented by this administration. Any route of administration known in the art may be used, including but not limited to oral, nasal, topical, intravenous, intraperitoneal, intradermal, mucosal, intrathecal, intramuscular, etc. Preferably, administration is oral.

However, to fully characterize the compositions as well as to determine the fate of the compositions following administration to a subject, antibodies to the specific GIT targeting agents are needed.

The present invention provides antibodies or antibody fragments specific to a domain of a GIT targeting agent, particularly antibodies to ZElan033 (PAX2 15 mer), ZElan088(HAX42-2 20 mer) and ZElan053 (P31 D-form 16 mer).

Additionally, numerous methods are provided below that employ the GIT targeting agent specific antibodies of this invention, including methods of detecting, quantitating, and locating the GIT targeting agent either in a pharmaceutical composition or after contact of a GIT targeting agent-containing composition with human or animal gastro-intestinal tissue.

FIG. 1 shows the immuno responses of three groups of 2 rabbits, each group immunized, respectively, with one of KLH conjugated ZElan033, KLH conjugated ZElan088 and KLH conjugated ZElan053, when the fourth bleed samples are tested by ELISA on their respective unconjugated peptides.

FIG. 2 shows the cross reactivity of rabbit antisera for three groups of 2 rabbits, each group immunized, respectively, with one of KLH conjugated ZElan033, KLH conjugated ZElan088 and KLH conjugated ZElan053, when the fourth bleed samples are tested by ELISA on each of synthetic peptides HAX42.2, PAX 2 15 mer and P31-D-form.

FIG. 3 shows the immuno-reactivity of anti-HAX42-2 antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan021 is SEQ ID NO:4 in the Sequence Listing herein. The sequence for Zelan071 is SEQ ID NO: 5, that for Zelan088 is SEQ ID NO:2, and that for Unconj. Antigen is SEQ ID NO:6.

FIG. 4 shows the immuno-reactivity of anti-PAX2 antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan108 is SEQ ID NO:7 in the Sequence Listing herein. The sequence for Zelan104 is SEQ ID NO: 8, that for Unconj.Ag is SEQ ID NO:1, and that for Zelan103A is SEQ ID NO:9.

FIG. 5 shows the immuno-reactivity of anti-P31 D-form antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan024 is SEQ ID NO:10 in the Sequence Listing herein. The sequence for Unconj.Ag is SEQ ID NO: 3, that for Zelan054 is SEQ ID NO:11, and that for ZElan145 is SEQ ID NO:12.

According to this invention, a GIT targeting agent may be used as an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and a Fab expression library. Particular antibodies provided by this invention include but are not limited to antibodies or antibody fragments, preferably polyclonal antibodies or antibody fragments, specific to a domain of GIT targeting agents ZElan033 (PAX2 15 mer), ZElan088 (HAX42-2 20 mer) and ZElan053 (P31 D-form 16 mer). Additional GIT targeting agents are disclosed throughout the above-referenced WO 98/51325.

The HPT1, hPEPT1, D2H, and hSI receptors were selected for cloning as GIT receptor targets based on several criteria, including: (1) expression on surface of epithelial cells in gastro-intestinal tract (GIT); (2) expression along the length of small intestine (HPT1, hPEPT1, D2H); (3) expression locally at high concentration (hSI); (4) large putative extracellular domains facing into the lumen of the GIT; and (5) extracellular domains that permit easy access and bioadhesion by targeting particles.

The four recombinant receptor sites screened with the peptide libraries additionally have the following characteristics:

The following receptor domains were cloned and expressed as His-tag fusion proteins by standard techniques:

Cloning of Extracellular Domain of Selected Receptor Site

The receptor proteins were expressed as His-tag fusion proteins and affinity purified under denaturing conditions, using urea or guanidine HCI, utilizing the pET His-tag metal chelate affinity for Ni-NTA Agarose (Hochuli, E., Purification of recombinant proteins with metal chelate adsorbent, Genetic Engineering, Principals and Methods (J. K. Setlow, ed.), Plenum Press, NY, Vol. 12 (1990), pp. 87-98).

As indicated in WO 98/51325, phage which showed specificity to a GIT receptor was further characterized by ELISA on a variety of recombinant proteins. Phage which continued to exhibit GIT receptor specificity was sequenced. Their insert sequences are summarized as follows:

These antibodies can be used in methods relating to the localization and activity of the GIT targeting agent sequences, e.g., for imaging these peptides after in vivo administration (e.g., to monitor treatment efficacy), measuring levels thereof in appropriate physiological samples, in diagnostic methods, etc. For instance, antibodies or antibody fragments specific to a domain of a GIT targeting agent, such as a dansyl group or some other epitope introduced into the peptide, can be used to 1) identify the presence of the peptide on a nanoparticle or other substrate; 2) quantify the amount of peptide on the nanoparticle; 3) measure the level of the peptide in appropriate physiological samples; 4) perform immunohistology on tissue samples; 5) image the peptide after in vivo administration; 6) purify the peptide from a mixture using an immunoaffinity column, 7) bind or fix the peptide to the surface of nanoparticle or 8) when a tag is also added to either an active-agent containing particle or the active agent itself, track the fate of both the particle/active agent and the GIT targeting agent so as to determine if and/or where they become separated. Use 7 above envisions attaching the antibody (or fragment of the antibody) to the surface of drug-loaded nanoparticles or other substrates and then incubating this conjugate with the peptide. This procedure results in binding of the peptide in a certain fixed orientation, resulting in a particle that contains the peptide bound to the antibody in such a way that the peptide is fully active. Additionally, antibodies or antibody fragments specific to a domain of a GIT targeting agent 9) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location or localization of the peptide on the surface of a nano- or microparticle, 10) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location or localization of the peptide on the surface of a nanoparticle or microparticle which has also been loaded with a fluorescent agent, 11) in the case of nanoparticles or microparticles coated with the peptide which have been sliced into two halves by a microtone or other suitable techniques, the antibody can be used in suitable quantitative techniques such as confocal microscopy imaging techniques or other quantitative imaging techniques in order to identify or quantitate the relative distribution of the peptide between the surface of the nanoparticle or microparticle and the sub-surface interior matrix of the nanoparticles or microparticles, 12) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location of a peptide on the surface of a nanoparticle or microparticle which has been loaded with a fluorescent agent such as TRME or fluorascene, 13) can be used to identify which epitope or domain of the peptide is responsible for identification by the antibody; peptide derivatives such as cyclic forms or derivatives containing intra-chain disulphide bonds or other intra-chain bonds can also be used in mapping studies in order to identify which domain or epitope of the peptide is responsible for recognition by the antibody; 14) in the case of peptide derivatives in which the epitope or domain responsible for binding to a target receptor is flanked by di-sulphide bond or other intra-chain bonds and in which this domain is also responsible for binding to the antibody, the antibody can be used to determine if that epitope or domain is exposed or available for binding to the antibody when the peptide or derivative is coated onto the surface of a nanoparticle, microparticle or other substance, 15) can be used where the epitope or domain on the peptide which binds to the target receptors in the human gastro-intestinal tract or the target receptors on model epithelial cells such as Caco-2 cells or polarised Caco-2 cells and where this epitope or domain on the peptide is also responsible for binding by the antibody, the antibody can be used in competition studies to compete for the binding of the peptide to its target receptor sites and 16) where the epitope or domain on the peptide which binds to the target receptors in the human gastro-intestinal or the target receptors on model epithelial cells such as Caco-2 cells or polarised Caco-2 cells and where this epitope or domain on the peptide is also responsible for binding by the antibody, the antibody can be used in competition studies in which nanoparticles or microparticles are coated with the peptide and are used in cell binding studies and/or in receptor binding studies.

Polyclonal antibodies against the GIT targeting agents PAX2 15 mer, HAX42-2 20mer and P31 D-form 16mer were raised to allow for, among other uses as discussed above, following the destiny of particles coated with peptides in in vivo models. These three GIT targeting agents were selected for their ability to bind in vitro to Caco-2 P100 fraction and, when coated on the surface of insulin loaded nanoparticles, to enhance insulin delivery in in vivo studies (rat model/intra-duodenal). The primary sequences for these three GIT targeting agents are given in Table 1.

The peptides were synthesised (Genosys) and conjugated to KLH protein in preparation to immunise rabbits. KLH protein was conjugated at both N- and C-terminals in order to maximise the probability of obtaining specific antibodies.

The immunization protocol provided that two rabbits were immunized for each peptide; Rabbits 122 and 123 were immunized with PAX215 mer, Rabbits 120 and 121 were immunized with HAX42-2 20 mer and Rabbits 141 and 142 were immunized with P31 D-form 16mer. The initial immunisation was given in Complete Freund's adjuvant and the remaining boosts in Incomplete Freunds. A pre-immune sample was taken from each animal before immunization. The rabbits were injected at day 0, day 14 and 28, bled a week later at day 35 (1 st bleed), boosted a week later at day 42 and bled a week later at day 49; this sequence of injections and bleeds was performed every two weeks.

The bleed samples were tested by ELISA using the following procedures: 96 well plates were coated with peptide at 50 μg/ml in 0.05M carbonate/bicarbonate buffer, pH9.6, overnight. The plates were washed twice with PBS+0.05% Tween20 and the plates were blocked with 2% dried skimmed milk (99% fat free) in PBS for one hour at room temperature. The plates were then washed three times with PBS+0.05% Tween20 and anti-sera diluted in 2% dried milk-PBS was added followed by incubation for one hour at room temperature. The plates were then washed three times with PBS+0.05% Tween20 and secondary antibody goat anti-rabbit IgG-HRP (Sigma A0545, dilution 1:20000) in 2% dried milk-PBS was added followed by incubation for one hour at room temperature. The plates were washed three times with PBS+0.05% Tween20, TMB substrate was added, incubated and the absorbance was read at 650 nm.

The fourth bleed samples were tested by ELISA on both the peptides used for immunisation (but not conjugated to KLH) and on different (dansylated) peptide batches. Pre-immune serum was included in the assay as negative control and background binding to plastic was also tested. As shown in FIG. 1, the antisera of the immunised rabbits gave an antibody response compared to pre-immune sera of the same animals. The immuno response of the two rabbits immunised in each protocol was comparable except that Rabbit 120 showed a lower antibody titer with respect to Rabbit 121. Crossreactivity of each rabbit antiserum on different peptides was also analysed by ELISA as shown in FIG. 2 and no significant cross-reactivity was detected.

The fifth bleed samples were tested by ELISA as described above and examples of the profiles obtained are shown in FIGS. 3, 4 and 5 . A higher titer of antibody was detected for each rabbit after this longer immunisation period compared to the fourth bleed results.

FIG. 3 shows the immuno-reaction of anti-HAX42 antisera on synthetic peptides (sequences reported in the Figure). Panel A shows the ELISA results for rabbit # 120 antisera: good immuno-response is obtained on unconjugated peptide used as antigen but no response was obtained for the same peptide conjugated to a dansyl group (Zelan088). No immuno-response is observed for the other peptides analysed. Panel B shows the ELISA results for rabbit # 121 antisera: in this case there also was good immuno-response for the unconjugated peptide used as antigen but no response for Zelan088 dansyl-peptide. Rabbit # 121 antisera is positive (although less strongly) against Zelan021 (HAX42) and Zelan071 (HAX42 29 mer derivative). Panel C shows the response of anti-dansyl IgG on the peptides used in the assay.

FIG. 4 shows the immuno-reactivity of anti-PAX2 antisera on synthetic peptides. Rabbit # 122 (panel A) and # 123 (panel B) have a different immuno-response. Both antisera react in the same way to the unconjugated peptide (=Zelan033) used for immunisation. Rabbit # 123 antisera has also very strong reactivity against Zelan103A peptide whereas rabbit # 122 does not bind to the same peptide. Rabbit # 123 antisera has also imuno-response against both Zelan104 and Zelan108. Panel C shows the response of anti-dansyl IgG on the peptides used in the assay.

FIG. 5 shows the immuno-reactivity of anti-P31 D-form antisera on synthetic peptides. Both rabbit # 141 and # 142 react equally well on P31 D-form unconjugated peptide (=Zelan053). No reactivity is present against all the other peptides tested.

Table 2 provides a summary of the fifth bleed results.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

84

1

15

Artificial Sequence

Random peptide

1

Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu Arg Thr Arg

1 5 10 15

2

20

Artificial Sequence

Random peptide

2

Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly

1 5 10 15

Asn Ser Thr Gly

20

3

16

Artificial Sequence

Random peptide

3

Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg Gly Arg Arg His Pro Gly

1 5 10 15

4

36

Artificial Sequence

Random peptide

4

Ser Asp His Ala Leu Gly Thr Asn Leu Arg Ser Asp Asn Ala Lys Glu

1 5 10 15

Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly Asn Ser Thr Gly Arg Lys

20 25 30

Val Phe Asn Arg

35

5

29

Artificial sequence

Random peptide

5

Asn Leu Arg Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys

1 5 10 15

Gly Asn Gly Asn Ser Thr Gly Arg Lys Val Phe Asn Arg

20 25

6

20

Artificial Sequence

Random sequence

6

Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly

1 5 10 15

Asn Ser Thr Gly

20

7

40

Artificial Sequence

Random peptide

7

Ser Thr Pro Pro Ser Arg Glu Ala Tyr Ser Arg Pro Tyr Ser Val Asp

1 5 10 15

Ser Asp Ser Asp Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu

20 25 30

Arg Thr Arg Ser Arg Pro Asn Gly

35 40

8

15

Artificial Sequence

Cyclic (internal) random peptide

8

Thr Asn Ala Lys His Ser Ser Cys Asn Arg Arg Leu Arg Cys Arg

1 5 10 15

9

15

Artificial Sequence

Cyclic (internal) random peptide

9

Thr Asn Ala Lys His Ser Ser Cys Asn Arg Arg Cys Arg Thr Arg

1 5 10 15

10

41

Artificial Sequence

Random peptide

10

Ser Ala Arg Asp Ser Gly Pro Ala Glu Asp Gly Ser Arg Ala Val Arg

1 5 10 15

Leu Asn Gly Val Glu Asn Ala Asn Thr Arg Lys Ser Ser Arg Ser Asn

20 25 30

Pro Arg Gly Arg Arg His Pro Gly Gly

35 40

11

16

Artificial Sequence

Random peptide

11

Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg Gly Arg Arg His Pro Gly

1 5 10 15

12

16

Artificial Sequence

Random peptide, D form, retroinversion

12

Gly Pro His Arg Arg Gly Arg Pro Asn Ser Arg Ser Ser Lys Arg Thr

1 5 10 15

13

685

Artificial

D2H receptor

13

Met Ala Glu Asp Lys Ser Lys Arg Asp Ser Ile Glu Met Ser Met Lys

1 5 10 15

Gly Cys Gln Thr Asn Asn Gly Phe Val His Asn Glu Asp Ile Leu Glu

20 25 30

Gln Thr Pro Asp Pro Gly Ser Ser Thr Asp Asn Leu Lys His Ser Thr

35 40 45

Arg Gly Ile Leu Gly Ser Gln Glu Pro Asp Phe Lys Gly Val Gln Pro

50 55 60

Tyr Ala Gly Met Pro Lys Glu Val Leu Phe Gln Phe Ser Gly Gln Ala

65 70 75 80

Arg Tyr Arg Ile Pro Arg Glu Ile Leu Phe Trp Leu Thr Val Ala Ser

85 90 95

Val Leu Val Leu Ile Ala Ala Thr Ile Ala Ile Ile Ala Leu Ser Pro

100 105 110

Lys Cys Leu Asp Trp Trp Gln Glu Gly Pro Met Tyr Gln Ile Tyr Pro

115 120 125

Arg Ser Phe Lys Asp Ser Asn Lys Asp Gly Asn Gly Asp Leu Lys Gly

130 135 140

Ile Gln Asp Lys Leu Asp Tyr Ile Thr Ala Leu Asn Ile Lys Thr Val

145 150 155 160

Trp Ile Thr Ser Phe Tyr Lys Ser Ser Leu Lys Asp Phe Arg Tyr Gly

165 170 175

Val Glu Asp Phe Arg Glu Val Asp Pro Ile Phe Gly Thr Met Glu Asp

180 185 190

Phe Glu Asn Leu Val Ala Ala Ile His Asp Lys Gly Leu Lys Leu Ile

195 200 205

Ile Asp Phe Ile Pro Asn His Thr Ser Asp Lys His Ile Trp Phe Gln

210 215 220

Leu Ser Arg Thr Arg Thr Gly Lys Tyr Thr Asp Tyr Tyr Ile Trp His

225 230 235 240

Asp Cys Thr His Glu Asn Gly Lys Thr Ile Pro Pro Asn Asn Trp Leu

245 250 255

Ser Val Tyr Gly Asn Ser Ser Trp His Phe Asp Glu Val Arg Asn Gln

260 265 270

Cys Tyr Phe His Gln Phe Met Lys Glu Gln Pro Asp Leu Asn Phe Arg

275 280 285

Asn Pro Asp Val Gln Glu Glu Ile Lys Glu Ile Leu Arg Phe Trp Leu

290 295 300

Thr Lys Gly Val Asp Gly Phe Ser Leu Asp Ala Val Lys Phe Leu Leu

305 310 315 320

Glu Ala Lys His Leu Arg Asp Glu Ile Gln Val Asn Lys Thr Gln Ile

325 330 335

Pro Asp Thr Val Thr Gln Tyr Ser Glu Leu Tyr His Asp Phe Thr Thr

340 345 350

Thr Gln Val Gly Met His Asp Ile Val Arg Ser Phe Arg Gln Thr Met

355 360 365

Asp Gln Tyr Ser Thr Glu Pro Gly Arg Tyr Arg Phe Met Gly Thr Glu

370 375 380

Ala Tyr Ala Glu Ser Ile Asp Arg Thr Val Met Tyr Tyr Gly Leu Pro

385 390 395 400

Phe Ile Gln Glu Ala Asp Phe Pro Phe Asn Asn Tyr Leu Ser Met Leu

405 410 415

Asp Thr Val Ser Gly Asn Ser Val Tyr Glu Val Ile Thr Ser Trp Met

420 425 430

Glu Asn Met Pro Glu Gly Lys Trp Pro Asn Trp Met Ile Gly Gly Pro

435 440 445

Asp Ser Ser Arg Leu Thr Ser Arg Leu Gly Asn Gln Tyr Val Asn Val

450 455 460

Met Asn Met Leu Leu Phe Thr Leu Pro Gly Thr Pro Ile Thr Tyr Tyr

465 470 475 480

Gly Glu Glu Ile Gly Met Gly Asn Ile Val Ala Ala Asn Leu Asn Glu

485 490 495

Ser Tyr Asp Ile Asn Thr Leu Arg Ser Lys Ser Pro Met Gln Trp Asp

500 505 510

Asn Ser Ser Asn Ala Gly Phe Ser Glu Ala Ser Asn Thr Trp Leu Pro

515 520 525

Thr Asn Ser Asp Tyr His Thr Val Asn Val Asp Val Gln Lys Thr Gln

530 535 540

Pro Arg Ser Ala Leu Lys Leu Tyr Gln Asp Leu Ser Leu Leu His Ala

545 550 555 560

Asn Glu Leu Leu Leu Asn Arg Gly Trp Phe Cys His Leu Arg Asn Asp

565 570 575

Ser His Tyr Val Val Tyr Thr Arg Glu Leu Asp Gly Ile Asp Arg Ile

580 585 590

Phe Ile Val Val Leu Asn Phe Gly Glu Ser Thr Leu Leu Asn Leu His

595 600 605

Asn Met Ile Ser Gly Leu Pro Ala Lys Ile Arg Ile Arg Leu Ser Thr

610 615 620

Asn Ser Ala Asp Lys Gly Ser Lys Val Asp Thr Ser Gly Ile Phe Leu

625 630 635 640

Asp Lys Gly Glu Gly Leu Ile Phe Glu His Asn Thr Lys Asn Leu Leu

645 650 655

His Arg Gln Thr Ala Phe Arg Asp Arg Cys Phe Val Ser Asn Arg Ala

660 665 670

Cys Tyr Ser Ser Val Leu Asn Ile Leu Tyr Thr Ser Cys

675 680 685

14

1827

Artificial

hSI receptor

14

Met Ala Arg Lys Lys Phe Ser Gly Leu Glu Ile Ser Leu Ile Val Leu

1 5 10 15

Phe Val Ile Val Thr Ile Ile Ala Ile Ala Leu Ile Val Val Leu Ala

20 25 30

Thr Lys Thr Pro Ala Val Asp Glu Ile Ser Asp Ser Thr Ser Thr Pro

35 40 45

Ala Thr Thr Arg Val Thr Thr Asn Pro Ser Asp Ser Gly Lys Cys Pro

50 55 60

Asn Val Leu Asn Asp Pro Val Asn Val Arg Ile Asn Cys Ile Pro Glu

65 70 75 80

Gln Phe Pro Thr Glu Gly Ile Cys Ala Gln Arg Gly Cys Cys Trp Arg

85 90 95

Pro Trp Asn Asp Ser Leu Ile Pro Trp Cys Phe Phe Val Asp Asn His

100 105 110

Gly Tyr Asn Val Gln Asp Met Thr Thr Thr Ser Ile Gly Val Glu Ala

115 120 125

Lys Leu Asn Arg Ile Pro Ser Pro Thr Leu Phe Gly Asn Asp Ile Asn

130 135 140

Ser Val Leu Phe Thr Thr Gln Asn Gln Thr Pro Asn Arg Phe Arg Phe

145 150 155 160

Lys Ile Thr Asp Pro Asn Asn Arg Arg Tyr Glu Val Pro His Gln Tyr

165 170 175

Val Lys Glu Phe Thr Gly Pro Thr Val Ser Asp Thr Leu Tyr Asp Val

180 185 190

Lys Val Ala Gln Asn Pro Phe Ser Ile Gln Val Ile Arg Lys Ser Asn

195 200 205

Gly Lys Thr Leu Phe Asp Thr Ser Ile Gly Pro Leu Val Tyr Ser Asp

210 215 220

Gln Tyr Leu Gln Ile Ser Ala Arg Leu Pro Ser Asp Tyr Ile Tyr Gly

225 230 235 240

Ile Gly Glu Gln Val His Lys Arg Phe Arg His Asp Leu Ser Trp Lys

245 250 255

Thr Trp Pro Ile Phe Thr Arg Asp Gln Leu Pro Gly Asp Asn Asn Asn

260 265 270

Asn Leu Tyr Gly His Gln Thr Phe Phe Met Cys Ile Glu Asp Thr Ser

275 280 285

Gly Lys Ser Phe Gly Val Phe Leu Met Asn Ser Asn Ala Met Glu Ile

290 295 300

Phe Ile Gln Pro Thr Pro Ile Val Thr Tyr Arg Val Thr Gly Gly Ile

305 310 315 320

Leu Asp Phe Tyr Ile Leu Leu Gly Asp Thr Pro Glu Gln Val Val Gln

325 330 335

Gln Tyr Gln Gln Leu Val Gly Leu Pro Ala Met Pro Ala Tyr Trp Asn

340 345 350

Leu Gly Phe Gln Leu Ser Arg Trp Asn Tyr Lys Ser Leu Asp Val Val

355 360 365

Lys Glu Val Val Arg Arg Asn Arg Glu Ala Gly Ile Pro Phe Asp Thr

370 375 380

Gln Val Thr Asp Ile Asp Tyr Met Glu Asp Lys Lys Asp Phe Thr Tyr

385 390 395 400

Asp Gln Val Ala Phe Asn Gly Leu Pro Gln Phe Val Gln Asp Leu His

405 410 415

Asp His Gly Gln Lys Tyr Val Ile Ile Leu Asp Pro Ala Ile Ser Ile

420 425 430

Gly Arg Arg Ala Asn Gly Thr Thr Tyr Ala Thr Tyr Glu Arg Gly Asn

435 440 445

Thr Gln His Val Trp Ile Asn Glu Ser Asp Gly Ser Thr Pro Ile Ile

450 455 460

Gly Glu Val Trp Pro Gly Leu Thr Val Tyr Pro Asp Phe Thr Asn Pro

465 470 475 480

Asn Cys Ile Asp Trp Trp Ala Asn Glu Cys Ser Ile Phe His Gln Glu

485 490 495

Val Gln Tyr Asp Gly Leu Trp Ile Asp Met Asn Glu Val Ser Ser Phe

500 505 510

Ile Gln Gly Ser Thr Lys Gly Cys Asn Val Asn Lys Leu Asn Tyr Pro

515 520 525

Pro Phe Thr Pro Asp Ile Leu Asp Lys Leu Met Tyr Ser Lys Thr Ile

530 535 540

Cys Met Asp Ala Val Gln Asn Trp Gly Lys Gln Tyr Asp Val His Ser

545 550 555 560

Leu Tyr Gly Tyr Ser Met Ala Ile Ala Thr Glu Gln Ala Val Gln Lys

565 570 575

Val Phe Pro Asn Lys Arg Ser Phe Ile Leu Thr Arg Ser Thr Phe Ala

580 585 590

Gly Ser Gly Arg His Ala Ala His Trp Leu Gly Asp Asn Thr Ala Ser

595 600 605

Trp Glu Gln Met Glu Trp Ser Ile Thr Gly Met Leu Glu Phe Ser Leu

610 615 620

Phe Gly Ile Pro Leu Val Gly Ala Asp Ile Cys Gly Phe Val Ala Glu

625 630 635 640

Thr Thr Glu Glu Leu Cys Arg Arg Trp Met Gln Leu Gly Ala Phe Tyr

645 650 655

Pro Phe Ser Arg Asn His Asn Ser Asp Gly Tyr Glu His Gln Asp Pro

660 665 670

Ala Phe Phe Gly Gln Asn Ser Leu Leu Val Lys Ser Ser Arg Gln Tyr

675 680 685

Leu Thr Ile Arg Tyr Thr Leu Leu Pro Phe Leu Tyr Thr Leu Phe Tyr

690 695 700

Lys Ala His Val Phe Gly Glu Thr Val Ala Arg Pro Val Leu His Glu

705 710 715 720

Phe Tyr Glu Asp Thr Asn Ser Trp Ile Glu Asp Thr Glu Phe Leu Trp

725 730 735

Gly Pro Ala Leu Leu Ile Thr Pro Val Leu Lys Gln Gly Ala Asp Thr

740 745 750

Val Ser Ala Tyr Ile Pro Asp Ala Ile Trp Tyr Asp Tyr Glu Ser Gly

755 760 765

Ala Lys Arg Pro Trp Arg Lys Gln Arg Val Asp Met Tyr Leu Pro Ala

770 775 780

Asp Lys Ile Gly Leu His Leu Arg Gly Gly Tyr Ile Ile Pro Ile Gln

785 790 795 800

Glu Pro Asp Val Thr Thr Thr Ala Ser Arg Lys Asn Pro Leu Gly Leu

805 810 815

Ile Val Ala Leu Gly Glu Asn Asn Thr Ala Lys Gly Asp Phe Phe Trp

820 825 830

Asp Asp Gly Glu Thr Lys Asp Thr Ile Gln Asn Gly Asn Tyr Ile Leu

835 840 845

Tyr Thr Phe Ser Val Ser Asn Asn Thr Leu Asp Ile Val Cys Thr His

850 855 860

Ser Ser Tyr Gln Glu Gly Thr Thr Leu Ala Phe Gln Thr Val Lys Ile

865 870 875 880

Leu Gly Leu Thr Asp Ser Val Thr Glu Val Arg Val Ala Glu Asn Asn

885 890 895

Gln Pro Met Asn Ala His Ser Asn Phe Thr Tyr Asp Ala Ser Asn Gln

900 905 910

Val Leu Leu Ile Ala Asp Leu Lys Leu Asn Leu Gly Arg Asn Phe Ser

915 920 925

Val Gln Trp Asn Gln Ile Phe Ser Glu Asn Glu Arg Phe Asn Cys Tyr

930 935 940

Pro Asp Ala Asp Leu Ala Thr Glu Gln Lys Cys Thr Gln Arg Gly Cys

945 950 955 960

Val Trp Arg Thr Gly Ser Ser Leu Ser Lys Ala Pro Glu Cys Tyr Phe

965 970 975

Pro Arg Gln Asp Asn Ser Tyr Ser Val Asn Ser Ala Arg Tyr Ser Ser

980 985 990

Met Gly Ile Thr Ala Asp Leu Gln Leu Asn Thr Ala Asn Ala Arg Ile

995 1000 1005

Lys Leu Pro Ser Asp Pro Ile Ser Thr Leu Arg Val Glu Val Lys

1010 1015 1020

Tyr His Lys Asn Asp Met Leu Gln Phe Lys Ile Tyr Asp Pro Gln

1025 1030 1035

Lys Lys Arg Tyr Glu Val Pro Val Pro Leu Asn Ile Pro Thr Thr

1040 1045 1050

Pro Ile Ser Thr Tyr Glu Asp Arg Leu Tyr Asp Val Glu Ile Lys

1055 1060 1065

Glu Asn Pro Phe Gly Ile Gln Ile Arg Arg Arg Ser Ser Gly Arg

1070 1075 1080

Val Ile Trp Asp Ser Trp Leu Pro Gly Phe Ala Phe Asn Asp Gln

1085 1090 1095

Phe Ile Gln Ile Ser Thr Arg Leu Pro Ser Glu Tyr Ile Tyr Gly

1100 1105 1110

Phe Gly Glu Val Glu His Thr Ala Phe Lys Arg Asp Leu Asn Trp

1115 1120 1125

Asn Thr Trp Gly Met Phe Thr Arg Asp Gln Pro Pro Gly Tyr Lys

1130 1135 1140

Leu Asn Ser Tyr Gly Phe His Pro Tyr Tyr Met Ala Leu Glu Glu

1145 1150 1155

Glu Gly Asn Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met

1160 1165 1170

Asp Val Thr Phe Gln Pro Thr Pro Ala Leu Thr Tyr Arg Thr Val

1175 1180 1185

Gly Gly Ile Leu Asp Phe Tyr Met Phe Leu Gly Pro Thr Pro Gln

1190 1195 1200

Val Ala Thr Lys Gln Tyr His Glu Val Ile Gly His Pro Val Met

1205 1210 1215

Pro Ala Tyr Trp Ala Leu Gly Phe Gln Leu Cys Arg Tyr Gly Tyr

1220 1225 1230

Ala Asn Thr Ser Glu Val Arg Glu Leu Tyr Asp Ala Met Val Ala

1235 1240 1245

Ala Asn Ile Pro Tyr Asp Val Gln Tyr Thr Asp Ile Asp Tyr Met

1250 1255 1260

Glu Arg Gln Leu Asp Phe Thr Ile Gly Glu Ala Phe Gln Asp Leu

1265 1270 1275

Pro Gln Phe Val Asp Lys Ile Arg Gly Glu Gly Met Arg Tyr Ile

1280 1285 1290

Ile Ile Leu Asp Pro Ala Ile Ser Gly Asn Glu Thr Lys Thr Tyr

1295 1300 1305

Pro Ala Phe Glu Arg Gly Gln Gln Asn Asp Val Phe Val Lys Trp

1310 1315 1320

Pro Asn Thr Asn Asp Ile Cys Trp Ala Lys Val Trp Pro Asp Leu

1325 1330 1335

Pro Asn Ile Thr Ile Asp Lys Thr Leu Thr Glu Asp Glu Ala Val

1340 1345 1350

Asn Ala Ser Arg Ala His Val Ala Phe Pro Asp Phe Phe Arg Thr

1355 1360 1365

Ser Thr Ala Glu Trp Trp Ala Arg Glu Ile Val Asp Phe Tyr Asn

1370 1375 1380

Glu Lys Met Lys Phe Asp Gly Leu Trp Ile Asp Met Asn Glu Pro

1385 1390 1395

Ser Ser Phe Val Asn Gly Thr Thr Thr Asn Gln Cys Arg Asn Asp

1400 1405 1410

Glu Leu Asn Tyr Pro Pro Tyr Phe Pro Glu Leu Thr Lys Arg Thr

1415 1420 1425

Asp Gly Leu His Phe Arg Thr Ile Cys Met Glu Ala Glu Gln Ile

1430 1435 1440

Leu Ser Asp Gly Thr Ser Val Leu His Tyr Asp Val His Asn Leu

1445 1450 1455

Tyr Gly Trp Ser Gln Met Lys Pro Thr His Asp Ala Leu Gln Lys

1460 1465 1470

Thr Thr Gly Lys Arg Gly Ile Val Ile Ser Arg Ser Thr Tyr Pro

1475 1480 1485

Thr Ser Gly Arg Trp Gly Gly His Trp Leu Gly Asp Asn Tyr Ala

1490 1495 1500

Arg Trp Asp Asn Met Asp Lys Ser Ile Ile Gly Met Met Glu Phe

1505 1510 1515

Ser Leu Phe Gly Ile Ser Tyr Thr Gly Ala Asp Ile Cys Gly Phe

1520 1525 1530

Phe Asn Asn Ser Glu Tyr His Leu Cys Thr Arg Trp Met Gln Leu

1535 1540 1545

Gly Ala Phe Tyr Pro Tyr Ser Arg Asn His Asn Ile Ala Asn Thr

1550 1555 1560

Arg Arg Gln Asp Pro Ala Ser Trp Asn Glu Thr Phe Ala Glu Met

1565 1570 1575

Ser Arg Asn Ile Leu Asn Ile Arg Tyr Thr Leu Leu Pro Tyr Phe

1580 1585 1590

Tyr Thr Gln Met His Glu Ile His Ala Asn Gly Gly Thr Val Ile

1595 1600 1605

Arg Pro Leu Leu His Glu Phe Phe Asp Glu Lys Pro Thr Trp Asp

1610 1615 1620

Ile Phe Lys Gln Phe Leu Trp Gly Pro Ala Phe Met Val Thr Pro

1625 1630 1635

Val Leu Glu Pro Tyr Val Gln Thr Val Asn Ala Tyr Val Pro Asn

1640 1645 1650

Ala Arg Trp Phe Asp Tyr His Thr Gly Lys Asp Ile Gly Val Arg

1655 1660 1665

Gly Gln Phe Gln Thr Phe Asn Ala Ser Tyr Asp Thr Ile Asn Leu

1670 1675 1680

His Val Arg Gly Gly His Ile Leu Pro Cys Gln Glu Pro Ala Gln

1685 1690 1695

Asn Thr Phe Tyr Ser Arg Gln Lys His Met Lys Leu Ile Val Ala

1700 1705 1710

Ala Asp Asp Asn Gln Met Ala Gln Gly Ser Leu Phe Trp Asp Asp

1715 1720 1725

Gly Glu Ser Ile Asp Thr Tyr Glu Arg Asp Leu Tyr Leu Ser Val

1730 1735 1740

Gln Phe Asn Leu Asn Gln Thr Thr Leu Thr Ser Thr Ile Leu Lys

1745 1750 1755

Arg Gly Tyr Ile Asn Lys Ser Glu Thr Arg Leu Gly Ser Leu His

1760 1765 1770

Val Trp Gly Lys Gly Thr Thr Pro Val Asn Ala Val Thr Leu Thr

1775 1780 1785

Tyr Asn Gly Asn Lys Asn Ser Leu Pro Phe Asn Glu Asp Thr Thr

1790 1795 1800

Asn Met Ile Leu Arg Ile Asp Leu Thr Thr His Asn Val Thr Leu

1805 1810 1815

Glu Glu Pro Ile Glu Ile Asn Trp Ser

1820 1825

15

832

Artificial

HPT1 receptor

15

Met Ile Leu Gln Ala His Leu His Ser Leu Cys Leu Leu Met Leu Tyr

1 5 10 15

Leu Ala Thr Gly Tyr Gly Gln Glu Gly Lys Phe Ser Gly Pro Leu Lys

20 25 30

Pro Met Thr Phe Ser Ile Tyr Glu Gly Gln Glu Pro Ser Gln Ile Ile

35 40 45

Phe Gln Phe Lys Ala Asn Pro Pro Ala Val Thr Phe Glu Leu Thr Gly

50 55 60

Glu Thr Asp Asn Ile Phe Val Ile Glu Arg Glu Gly Leu Leu Tyr Tyr

65 70 75 80

Asn Arg Ala Leu Asp Arg Glu Thr Arg Ser Thr His Asn Leu Gln Val

85 90 95

Ala Ala Leu Asp Ala Asn Gly Ile Ile Val Glu Gly Pro Val Pro Ile

100 105 110

Thr Ile Glu Val Lys Asp Ile Asn Asp Asn Arg Pro Thr Phe Leu Gln

115 120 125

Ser Lys Tyr Glu Gly Ser Val Arg Gln Asn Ser Arg Pro Gly Lys Pro

130 135 140

Phe Leu Tyr Val Asn Ala Thr Asp Leu Asp Asp Pro Ala Thr Pro Asn

145 150 155 160

Gly Gln Leu Tyr Tyr Gln Ile Val Ile Gln Leu Pro Met Ile Asn Asn

165 170 175

Val Met Tyr Phe Gln Ile Asn Asn Lys Thr Gly Ala Ile Ser Leu Thr

180 185 190

Arg Glu Gly Ser Gln Glu Leu Asn Pro Ala Lys Asn Pro Ser Tyr Asn

195 200 205

Leu Val Ile Ser Val Lys Asp Met Gly Gly Gln Ser Glu Asn Ser Phe

210 215 220

Ser Asp Thr Thr Ser Val Asp Ile Ile Val Thr Glu Asn Ile Trp Lys

225 230 235 240

Ala Pro Lys Pro Val Glu Met Val Glu Asn Ser Thr Asp Pro His Pro

245 250 255

Ile Lys Ile Thr Gln Val Arg Trp Asn Asp Pro Gly Ala Gln Tyr Ser

260 265 270

Leu Val Asp Lys Glu Lys Leu Pro Arg Phe Pro Phe Ser Ile Asp Gln

275 280 285

Glu Gly Asp Ile Tyr Val Thr Gln Pro Leu Asp Arg Glu Glu Lys Asp

290 295 300

Ala Tyr Val Phe Tyr Ala Val Ala Lys Asp Glu Tyr Gly Lys Pro Leu

305 310 315 320

Ser Tyr Pro Leu Glu Ile His Val Lys Val Lys Asp Ile Asn Asp Asn

325 330 335

Pro Pro Thr Cys Pro Ser Pro Val Thr Val Phe Glu Val Gln Glu Asn

340 345 350

Glu Arg Leu Gly Asn Ser Ile Gly Thr Leu Thr Ala His Asp Arg Asp

355 360 365

Glu Glu Asn Thr Ala Asn Ser Phe Leu Asn Tyr Arg Ile Val Glu Gln

370 375 380

Thr Pro Lys Leu Pro Met Asp Gly Leu Phe Leu Ile Gln Thr Tyr Ala

385 390 395 400

Gly Met Leu Gln Leu Ala Lys Gln Ser Leu Lys Lys Gln Asp Thr Pro

405 410 415

Gln Tyr Asn Leu Thr Ile Glu Val Ser Asp Lys Asp Phe Lys Thr Leu

420 425 430

Cys Phe Val Gln Ile Asn Val Ile Asp Ile Asn Asp Gln Ile Pro Ile

435 440 445

Phe Glu Lys Ser Asp Tyr Gly Asn Leu Thr Leu Ala Glu Asp Thr Asn

450 455 460

Ile Gly Ser Thr Ile Leu Thr Ile Gln Ala Thr Asp Ala Asp Glu Pro

465 470 475 480

Phe Thr Gly Ser Ser Lys Ile Leu Tyr His Ile Ile Lys Gly Asp Ser

485 490 495

Glu Gly Arg Leu Gly Val Asp Thr Asp Pro His Thr Asn Thr Gly Tyr

500 505 510

Val Ile Ile Lys Lys Pro Leu Asp Phe Glu Thr Ala Ala Val Ser Asn

515 520 525

Ile Val Phe Lys Ala Glu Asn Pro Glu Pro Leu Val Phe Gly Val Lys

530 535 540

Tyr Asn Ala Ser Ser Phe Ala Lys Phe Thr Leu Ile Val Thr Asp Val

545 550 555 560

Asn Glu Ala Pro Gln Phe Ser Gln His Val Phe Gln Ala Lys Val Ser

565 570 575

Glu Asp Val Ala Ile Gly Thr Lys Val Gly Asn Val Thr Ala Lys Asp

580 585 590

Pro Glu Gly Leu Asp Ile Ser Tyr Ser Leu Arg Gly Asp Thr Arg Gly

595 600 605

Trp Leu Lys Ile Asp His Val Thr Gly Glu Ile Phe Ser Val Ala Pro

610 615 620

Leu Asp Arg Glu Ala Gly Ser Pro Tyr Arg Val Gln Val Val Ala Thr

625 630 635 640

Glu Val Gly Gly Ser Ser Leu Ser Ser Val Ser Glu Phe His Leu Ile

645 650 655

Leu Met Asp Val Asn Asp Asn Pro Pro Arg Leu Ala Lys Asp Tyr Thr

660 665 670

Gly Leu Phe Phe Cys His Pro Leu Ser Ala Pro Gly Ser Leu Ile Phe

675 680 685

Glu Ala Thr Asp Asp Asp Gln His Leu Phe Arg Gly Pro His Phe Thr

690 695 700

Phe Ser Leu Gly Ser Gly Ser Leu Gln Asn Asp Trp Glu Val Ser Lys

705 710 715 720

Ile Asn Gly Thr His Ala Arg Leu Ser Thr Arg His Thr Asp Phe Glu

725 730 735

Glu Arg Ala Tyr Val Val Leu Ile Arg Ile Asn Asp Gly Gly Arg Pro

740 745 750

Pro Leu Glu Gly Ile Val Ser Leu Pro Val Thr Phe Cys Ser Cys Val

755 760 765

Glu Gly Ser Cys Phe Arg Pro Ala Gly His Gln Thr Gly Ile Pro Thr

770 775 780

Val Gly Met Ala Val Gly Ile Leu Leu Thr Thr Leu Leu Val Ile Gly

785 790 795 800

Ile Ile Leu Ala Val Val Phe Ile Arg Ile Lys Lys Asp Lys Gly Lys

805 810 815

Asp Asn Val Glu Ser Ala Gln Ala Ser Glu Val Lys Pro Leu Arg Ser

820 825 830

16

708

Artificial

hPEPT1 receptor

16

Met Gly Met Ser Lys Ser His Ser Phe Phe Gly Tyr Pro Leu Ser Ile

1 5 10 15

Phe Phe Ile Val Val Asn Glu Phe Cys Glu Arg Phe Ser Tyr Tyr Gly

20 25 30

Met Arg Ala Ile Leu Ile Leu Tyr Phe Thr Asn Phe Ile Ser Trp Asp

35 40 45

Asp Asn Leu Ser Thr Ala Ile Tyr His Thr Phe Val Ala Leu Cys Tyr

50 55 60

Leu Thr Pro Ile Leu Gly Ala Leu Ile Ala Asp Ser Trp Leu Gly Lys

65 70 75 80

Phe Lys Thr Ile Val Ser Leu Ser Ile Val Tyr Thr Ile Gly Gln Ala

85 90 95

Val Thr Ser Val Ser Ser Ile Asn Asp Leu Thr Asp His Asn His Asp

100 105 110

Gly Thr Pro Asp Ser Leu Pro Val His Val Val Leu Ser Leu Ile Gly

115 120 125

Leu Ala Leu Ile Ala Leu Gly Thr Gly Gly Ile Lys Pro Cys Val Ser

130 135 140

Ala Phe Gly Gly Asp Gln Phe Glu Glu Gly Gln Glu Lys Gln Arg Asn

145 150 155 160

Arg Phe Phe Ser Ile Phe Tyr Leu Ala Ile Asn Ala Gly Ser Leu Leu

165 170 175

Ser Thr Ile Ile Thr Pro Met Leu Arg Val Gln Gln Cys Gly Ile His

180 185 190

Ser Lys Gln Ala Cys Tyr Pro Leu Ala Phe Gly Val Pro Ala Ala Leu

195 200 205

Met Ala Val Ala Leu Ile Val Phe Val Leu Gly Ser Gly Met Tyr Lys

210 215 220

Lys Phe Lys Pro Gln Gly Asn Ile Met Gly Lys Val Ala Lys Cys Ile

225 230 235 240

Gly Phe Ala Ile Lys Asn Arg Phe Arg His Arg Ser Lys Ala Phe Pro

245 250 255

Lys Arg Glu His Trp Leu Asp Trp Ala Lys Glu Lys Tyr Asp Glu Arg

260 265 270

Leu Ile Ser Gln Ile Lys Met Val Thr Arg Val Met Phe Leu Tyr Ile

275 280 285

Pro Leu Pro Met Phe Trp Ala Leu Phe Asp Gln Gln Gly Ser Arg Trp

290 295 300

Thr Leu Gln Ala Thr Thr Met Ser Gly Lys Ile Gly Ala Leu Glu Ile

305 310 315 320

Gln Pro Asp Gln Met Gln Thr Val Asn Ala Ile Leu Ile Val Ile Met

325 330 335

Val Pro Ile Phe Asp Ala Val Leu Tyr Pro Leu Ile Ala Lys Cys Gly

340 345 350

Phe Asn Phe Thr Ser Leu Lys Lys Met Ala Val Gly Met Val Leu Ala

355 360 365

Ser Met Ala Phe Val Val Ala Ala Ile Val Gln Val Glu Ile Asp Lys

370 375 380

Thr Leu Pro Val Phe Pro Lys Gly Asn Glu Val Gln Ile Lys Val Leu

385 390 395 400

Asn Ile Gly Asn Asn Thr Met Asn Ile Ser Leu Pro Gly Glu Met Val

405 410 415

Thr Leu Gly Pro Met Ser Gln Thr Asn Ala Phe Met Thr Phe Asp Val

420 425 430

Asn Lys Leu Thr Arg Ile Asn Ile Ser Ser Pro Gly Ser Pro Val Thr

435 440 445

Ala Val Thr Asp Asp Phe Lys Gln Gly Gln Arg His Thr Leu Leu Val

450 455 460

Trp Ala Pro Asn His Tyr Gln Val Val Lys Asp Gly Leu Asn Gln Lys

465 470 475 480

Pro Glu Lys Gly Glu Asn Gly Ile Arg Phe Val Asn Thr Phe Asn Glu

485 490 495

Leu Ile Thr Ile Thr Met Ser Gly Lys Val Tyr Ala Asn Ile Ser Ser

500 505 510

Tyr Asn Ala Ser Thr Tyr Gln Phe Phe Pro Ser Gly Ile Lys Gly Phe

515 520 525

Thr Ile Ser Ser Thr Glu Ile Pro Pro Gln Cys Gln Pro Asn Phe Asn

530 535 540

Thr Phe Tyr Leu Glu Phe Gly Ser Ala Tyr Thr Tyr Ile Val Gln Arg

545 550 555 560

Lys Asn Asp Ser Cys Pro Glu Val Lys Val Phe Glu Asp Ile Ser Ala

565 570 575

Asn Thr Val Asn Met Ala Leu Gln Ile Pro Gln Tyr Phe Leu Leu Thr

580 585 590

Cys Gly Glu Val Val Phe Ser Val Thr Gly Leu Glu Phe Ser Tyr Ser

595 600 605

Gln Ala Pro Ser Asn Met Lys Ser Val Leu Gln Ala Gly Trp Leu Leu

610 615 620

Thr Val Ala Val Gly Asn Ile Ile Val Leu Ile Val Ala Gly Ala Gly

625 630 635 640

Gln Phe Ser Lys Gln Trp Ala Glu Tyr Ile Leu Phe Ala Ala Leu Leu

645 650 655

Leu Val Val Cys Val Val Phe Ala Ile Met Ala Arg Phe Tyr Thr Tyr

660 665 670

Ile Asn Pro Ala Glu Ile Glu Ala Gln Phe Asp Glu Asp Glu Lys Lys

675 680 685

Asn Arg Leu Glu Lys Ser Asn Pro Tyr Phe Met Ser Gly Ala Asn Ser

690 695 700

Gln Lys Gln Met

705

17

44

Artificial

S15 44 mer fragment L-form

17

Arg Ser Gly Ala Tyr Glu Ser Pro Asp Gly Arg Gly Gly Arg Ser Tyr

1 5 10 15

Val Gly Gly Gly Gly Gly Cys Gly Asn Ile Gly Arg Lys His Asn Leu

20 25 30

Trp Gly Leu Arg Thr Ala Ser Pro Ala Cys Trp Asp

35 40

18

44

Artificial

S21 44 mer fragment L-form

18

Ser Pro Arg Ser Phe Trp Pro Val Val Ser Arg His Glu Ser Phe Gly

1 5 10 15

Ile Ser Asn Tyr Leu Gly Cys Gly Tyr Arg Thr Cys Ile Ser Gly Thr

20 25 30

Met Thr Lys Ser Ser Pro Ile Tyr Pro Arg His Ser

35 40

19

44

Artificial

S22 44 mer fragment L-form

19

Ser Ser Ser Ser Asp Trp Gly Gly Val Pro Gly Lys Val Val Arg Glu

1 5 10 15

Arg Phe Lys Gly Arg Gly Cys Gly Ile Ser Ile Thr Ser Val Leu Thr

20 25 30

Gly Lys Pro Asn Pro Cys Pro Glu Pro Lys Ala Ala

35 40

20

44

Artificial

Sni10 44 mer fragment L-form

20

Arg Val Gly Gln Cys Thr Asp Ser Asp Val Arg Arg Pro Trp Ala Arg

1 5 10 15

Ser Cys Ala His Gln Gly Cys Gly Ala Gly Thr Arg Asn Ser His Gly

20 25 30

Cys Ile Thr Arg Pro Leu Arg Gln Ala Ser Ala His

35 40

21

39

Artificial

Sni28 39 mer fragment L-form

21

Ser His Ser Gly Gly Met Asn Arg Ala Tyr Gly Asp Val Phe Arg Glu

1 5 10 15

Leu Arg Asp Arg Trp Asn Ala Thr Ser His His Thr Arg Pro Thr Pro

20 25 30

Gln Leu Pro Arg Gly Pro Asn

35

22

41

Artificial

Sni34 41 mer fragment L-form

22

Ser Pro Cys Gly Gly Ser Trp Gly Arg Phe Met Gln Gly Gly Leu Phe

1 5 10 15

Gly Gly Arg Thr Asp Gly Cys Gly Ala His Arg Asn Arg Thr Ser Ala

20 25 30

Ser Leu Glu Pro Pro Ser Ser Asp Tyr

35 40

23

39

Artificial

Sni38 39 mer fragment L-form

23

Arg Gly Ala Ala Asp Gln Arg Arg Gly Trp Ser Glu Asn Leu Gly Leu

1 5 10 15

Pro Arg Val Gly Trp Asp Ala Ile Ala His Asn Ser Tyr Thr Phe Thr

20 25 30

Ser Arg Arg Pro Arg Pro Pro

35

24

44

Artificial

Sni45 44 mer fragment L-form

24

Ser Gly Gly Glu Val Ser Ser Trp Gly Arg Val Asn Asp Leu Cys Ala

1 5 10 15

Arg Val Ser Trp Thr Gly Cys Gly Thr Ala Arg Ser Ala Arg Thr Asp

20 25 30

Asn Lys Gly Phe Leu Pro Lys His Ser Ser Leu Arg

35 40

25

44

Artificial

SniAX2 44 mer fragment L-form

25

Ser Asp Ser Asp Gly Asp His Tyr Gly Leu Arg Gly Gly Val Arg Cys

1 5 10 15

Ser Leu Arg Asp Arg Gly Cys Gly Leu Ala Leu Ser Thr Val His Ala

20 25 30

Gly Pro Pro Ser Phe Tyr Pro Lys Leu Ser Ser Pro

35 40

26

39

Artificial

SniAX4 39 mer fragment L-form

26

Arg Ser Leu Gly Asn Tyr Gly Val Thr Gly Thr Val Asp Val Thr Val

1 5 10 15

Leu Pro Met Pro Gly His Ala Asn His Leu Gly Val Ser Ser Ala Ser

20 25 30

Ser Ser Asp Pro Pro Arg Arg

35

27

38

Artificial

SniAX6 38 mer fragment L-form

27

Arg Thr Thr Thr Ala Lys Gly Cys Leu Leu Gly Ser Phe Gly Val Leu

1 5 10 15

Ser Gly Cys Ser Phe Thr Pro Thr Ser Pro Pro Pro His Leu Gly Tyr

20 25 30

Pro Pro His Ser Val Asn

35

28

39

Artificial

SniAX8 39 mer fragment L-form

28

Ser Pro Lys Leu Ser Ser Val Gly Val Met Thr Lys Val Thr Glu Leu

1 5 10 15

Pro Thr Glu Gly Pro Asn Ala Ile Ser Ile Pro Ile Ser Ala Thr Leu

20 25 30

Gly Pro Arg Asn Pro Leu Arg

35

29

39

Artificial

DAB3 39 mer fragment L-form

29

Arg Trp Cys Gly Ala Glu Leu Cys Asn Ser Val Thr Lys Lys Phe Arg

1 5 10 15

Pro Gly Trp Arg Asp His Ala Asn Pro Ser Thr His His Arg Thr Pro

20 25 30

Pro Pro Ser Gln Ser Ser Pro

35

30

44

Artificial

DAB7 44 mer fragment L-form

30

Arg Trp Cys Gly Ala Asp Asp Pro Cys Gly Ala Ser Arg Trp Arg Gly

1 5 10 15

Gly Asn Ser Leu Phe Gly Cys Gly Leu Arg Cys Ser Ala Ala Gln Ser

20 25 30

Thr Pro Ser Gly Arg Ile His Ser Thr Ser Thr Ser

35 40

31

39

Artificial

DAB10 39 mer fragment L-form

31

Ser Lys Ser Gly Glu Gly Gly Asp Ser Ser Arg Gly Glu Thr Gly Trp

1 5 10 15

Ala Arg Val Arg Ser His Ala Met Thr Ala Gly Arg Phe Arg Trp Tyr

20 25 30

Asn Gln Leu Pro Ser Asp Arg

35

32

38

Artificial

DAB18 38 mer fragment L-form

32

Arg Ser Ser Ala Asn Asn Cys Glu Trp Lys Ser Asp Trp Met Arg Arg

1 5 10 15

Ala Cys Ile Ala Arg Tyr Ala Asn Ser Ser Gly Pro Ala Arg Ala Val

20 25 30

Asp Thr Lys Ala Ala Pro

35

33

44

Artificial

DAB24 44 mer fragment L-form

33

Ser Lys Trp Ser Trp Ser Ser Arg Trp Gly Ser Pro Gln Asp Lys Val

1 5 10 15

Glu Lys Thr Arg Ala Gly Cys Gly Gly Ser Pro Ser Ser Thr Asn Cys

20 25 30

His Pro Tyr Thr Phe Ala Pro Pro Pro Gln Ala Gly

35 40

34

44

Artificial

DAB30 44 mer fragment L-form

34

Ser Gly Phe Trp Glu Phe Ser Arg Gly Leu Trp Asp Gly Glu Asn Arg

1 5 10 15

Lys Ser Val Arg Ser Gly Cys Gly Phe Arg Gly Ser Ser Ala Gln Gly

20 25 30

Pro Cys Pro Val Thr Pro Ala Thr Ile Asp Lys His

35 40

35

44

Artificial

DAX15 44 mer fragment L-form

35

Ser Glu Ser Gly Arg Cys Arg Ser Val Ser Arg Trp Met Thr Thr Trp

1 5 10 15

Gln Thr Gln Lys Gly Gly Cys Gly Ser Asn Val Ser Arg Gly Ser Pro

20 25 30

Leu Asp Pro Ser His Gln Thr Gly His Ala Thr Thr

35 40

36

39

Artificial

DAX23 39 mer fragment L-form

36

Arg Glu Trp Arg Phe Ala Gly Pro Pro Leu Asp Leu Trp Ala Gly Pro

1 5 10 15

Ser Leu Pro Ser Phe Asn Ala Ser Ser His Pro Arg Ala Leu Arg Thr

20 25 30

Tyr Trp Ser Gln Arg Pro Arg

35

37

44

Artificial

DAX24 44 mer fragment L-form

37

Arg Met Glu Asp Ile Lys Asn Ser Gly Trp Arg Asp Ser Cys Arg Trp

1 5 10 15

Gly Asp Leu Arg Pro Gly Cys Gly Ser Arg Gln Trp Tyr Pro Ser Asn

20 25 30

Met Arg Ser Ser Arg Asp Tyr Pro Ala Gly Gly His

35 40

38

36

Artificial

DAX27 36 mer fragment L-form

38

Ser His Pro Trp Tyr Arg His Trp Asn His Gly Asp Phe Ser Gly Ser

1 5 10 15

Gly Gln Ser Arg His Thr Pro Pro Glu Ser Pro His Pro Gly Arg Pro

20 25 30

Asn Ala Thr Ile

35

39

44

Artificial

DCX8 44 mer fragment L-form

39

Arg Tyr Lys His Asp Ile Gly Cys Asp Ala Gly Val Asp Lys Lys Ser

1 5 10 15

Ser Ser Val Arg Gly Gly Cys Gly Ala His Ser Ser Pro Pro Arg Ala

20 25 30

Gly Arg Gly Pro Arg Gly Thr Met Val Ser Arg Leu

35 40

40

44

Artificial

DCX11 44 mer fragment L-form

40

Ser Gln Gly Ser Lys Gln Cys Met Gln Tyr Arg Thr Gly Arg Leu Thr

1 5 10 15

Val Gly Ser Glu Tyr Gly Cys Gly Met Asn Pro Ala Arg His Ala Thr

20 25 30

Pro Ala Tyr Pro Ala Arg Leu Leu Pro Arg Tyr Arg

35 40

41

44

Artificial

DCX26 44 mer fragment L-form

41

Ser Gly Arg Thr Thr Ser Glu Ile Ser Gly Leu Trp Gly Trp Gly Asp

1 5 10 15

Asp Arg Ser Gly Tyr Gly Trp Gly Asn Thr Leu Arg Pro Asn Tyr Ile

20 25 30

Pro Tyr Arg Gln Ala Thr Asn Arg His Arg Tyr Thr

35 40

42

39

Artificial

DCX33 39 mer fragment L-form

42

Arg Trp Asn Trp Thr Val Leu Pro Ala Thr Gly Gly His Tyr Trp Thr

1 5 10 15

Arg Ser Thr Asp Tyr His Ala Ile Asn Asn His Arg Pro Ser Ile Pro

20 25 30

His Gln His Pro Thr Pro Ile

35

43

44

Artificial

DCX36 44 mer fragment L-form

43

Ser Trp Ser Ser Trp Asn Trp Ser Ser Lys Thr Thr Arg Leu Gly Asp

1 5 10 15

Arg Ala Thr Arg Glu Gly Cys Gly Pro Ser Gln Ser Asp Gly Cys Pro

20 25 30

Tyr Asn Gly Arg Leu Thr Thr Val Lys Pro Arg Thr

35 40

44

37

Artificial

DCX39 37 mer fragment L-form

44

Ser Gly Ser Leu Asn Ala Trp Gln Pro Arg Ser Trp Val Gly Gly Ala

1 5 10 15

Phe Arg Ser His Ala Asn Asn Asn Leu Asn Pro Lys Pro Thr Met Val

20 25 30

Thr Arg His Pro Thr

35

45

44

Artificial

DCX42 44 mer fragment L-form

45

Arg Tyr Ser Gly Leu Ser Pro Arg Asp Asn Gly Pro Ala Cys Ser Gln

1 5 10 15

Glu Ala Thr Leu Glu Gly Cys Gly Ala Gln Arg Leu Met Ser Thr Arg

20 25 30

Arg Lys Gly Arg Asn Ser Arg Pro Gly Trp Thr Leu

35 40

46

39

Artificial

DCX45 39 mer fragment L-form

46

Ser Val Gly Asn Asp Lys Thr Ser Arg Pro Val Ser Phe Tyr Gly Arg

1 5 10 15

Val Ser Asp Leu Trp Asn Ala Ser Leu Met Pro Lys Arg Thr Pro Ser

20 25 30

Ser Lys Arg His Asp Asp Gly

35

47

38

Artificial

PAX9 38 mer fragment L-form

47

Arg Trp Pro Ser Val Gly Tyr Lys Gly Asn Gly Ser Asp Thr Ile Asp

1 5 10 15

Val His Ser Asn Asp Ala Ser Thr Lys Arg Ser Leu Ile Tyr Asn His

20 25 30

Arg Arg Pro Leu Phe Pro

35

48

39

Artificial

PAX14 39 mer fragment L-form

48

Arg Thr Phe Glu Asn Asp Gly Leu Gly Val Gly Arg Ser Ile Gln Lys

1 5 10 15

Lys Ser Asp Arg Trp Tyr Ala Ser His Asn Ile Arg Ser His Phe Ala

20 25 30

Ser Met Ser Pro Ala Gly Lys

35

49

44

Artificial

PAX15 44 mer fragment L-form

49

Ser Tyr Cys Arg Val Lys Gly Gly Gly Glu Gly Gly His Thr Asp Ser

1 5 10 15

Asn Leu Ala Arg Ser Gly Cys Gly Lys Val Ala Arg Thr Ser Arg Leu

20 25 30

Gln His Ile Asn Pro Arg Ala Thr Pro Pro Ser Arg

35 40

50

39

Artificial

PAX16 39 mer fragment L-form

50

Ser Trp Thr Arg Trp Gly Lys His Thr His Gly Gly Phe Val Asn Lys

1 5 10 15

Ser Pro Pro Gly Lys Asn Ala Thr Ser Pro Tyr Thr Asp Ala Gln Leu

20 25 30

Pro Ser Asp Gln Gly Pro Pro

35

51

44

Artificial

PAX17 44 mer fragment L-form

51

Ser Gln Val Asp Ser Phe Arg Asn Ser Phe Arg Trp Tyr Glu Pro Ser

1 5 10 15

Arg Ala Leu Cys His Gly Cys Gly Lys Arg Asp Thr Ser Thr Thr Arg

20 25 30

Ile His Asn Ser Pro Ser Asp Ser Tyr Pro Thr Arg

35 40

52

39

Artificial

PAX18 39 mer fragment L-form

52

Ser Phe Leu Arg Phe Gln Ser Pro Arg Phe Glu Asp Tyr Ser Arg Thr

1 5 10 15

Ile Ser Arg Leu Arg Asn Ala Thr Asn Pro Ser Asn Val Ser Asp Ala

20 25 30

His Asn Asn Arg Ala Leu Ala

35

53

39

Artificial

PAX35 39 mer fragment L-form

53

Arg Ser Ile Thr Asp Gly Gly Leu Asn Glu Val Asp Leu Ser Ser Val

1 5 10 15

Ser Asn Val Leu Glu Asn Ala Asn Ser His Arg Ala Tyr Arg Lys His

20 25 30

Arg Pro Thr Leu Lys Arg Pro

35

54

44

Artificial

PAX38 44 mer fragment L-form

54

Ser Ser Lys Val Ser Ser Pro Arg Asp Pro Thr Val Pro Arg Lys Gly

1 5 10 15

Gly Asn Val Asp Tyr Gly Cys Gly His Arg Ser Ser Ala Arg Met Pro

20 25 30

Thr Ser Ala Leu Ser Ser Ile Thr Lys Cys Tyr Thr

35 40

55

44

Artificial

PAX40 44 mer fragment L-form

55

Arg Ala Ser Thr Gln Gly Gly Arg Gly Val Ala Pro Glu Phe Gly Ala

1 5 10 15

Ser Val Leu Gly Arg Gly Cys Gly Ser Ala Thr Tyr Tyr Thr Asn Ser

20 25 30

Thr Ser Cys Lys Asp Ala Met Gly His Asn Tyr Ser

35 40

56

39

Artificial

PAX43 39 mer fragment L-form

56

Arg Trp Cys Glu Lys His Lys Phe Thr Ala Ala Arg Cys Ser Ala Gly

1 5 10 15

Ala Gly Phe Glu Arg Asp Ala Ser Arg Pro Pro Gln Pro Ala His Arg

20 25 30

Asp Asn Thr Asn Arg Asn Ala

35

57

39

Artificial

PAX45 39 mer fragment L-form

57

Ser Phe Gln Val Tyr Pro Asp His Gly Leu Glu Arg His Ala Leu Asp

1 5 10 15

Gly Thr Gly Pro Leu Tyr Ala Met Pro Gly Arg Trp Leu Arg Ala Arg

20 25 30

Pro Gln Asn Arg Asp Arg Gln

35

58

38

Artificial

PAX46 38 mer fragment L-form

58

Ser Arg Cys Thr Asp Asn Glu Gln Cys Pro Asp Thr Gly Thr Arg Ser

1 5 10 15

Arg Ser Val Ser Asn Ala Arg Tyr Phe Ser Ser Arg Leu Leu Lys Thr

20 25 30

His Ala Pro His Arg Pro

35

59

39

Artificial

P31 39 mer fragment L-form

59

Ser Ala Arg Asp Ser Gly Pro Ala Glu Asp Gly Ser Arg Ala Val Arg

1 5 10 15

Leu Asn Gly Val Glu Asn Ala Asn Thr Arg Lys Ser Ser Arg Ser Asn

20 25 30

Pro Arg Gly Arg Arg His Pro

35

60

44

Artificial

P90 44 mer fragment L-form

60

Ser Ser Ala Asp Ala Glu Lys Cys Ala Gly Ser Leu Leu Trp Trp Gly

1 5 10 15

Arg Gln Asn Asn Ser Gly Cys Gly Ser Pro Thr Lys Lys His Leu Lys

20 25 30

His Arg Asn Arg Ser Gln Thr Ser Ser Ser Ser His

35 40

61

39

Artificial

5PAX3 39 mer fragment L-form

61

Arg Pro Lys Asn Val Ala Asp Ala Tyr Ser Ser Gln Asp Gly Ala Ala

1 5 10 15

Ala Glu Glu Thr Ser His Ala Ser Asn Ala Ala Arg Lys Ser Pro Lys

20 25 30

His Lys Pro Leu Arg Arg Pro

35

62

39

Artificial

5PAX5 39 mer fragment L-form

62

Arg Gly Ser Thr Gly Thr Ala Gly Gly Glu Arg Ser Gly Val Leu Asn

1 5 10 15

Leu His Thr Arg Asp Asn Ala Ser Gly Ser Gly Phe Lys Pro Trp Tyr

20 25 30

Pro Ser Asn Arg Gly His Lys

35

63

39

Artificial

5PAX7 39 mer fragment L-form

63

Arg Trp Gly Trp Glu Arg Ser Pro Ser Asp Tyr Asp Ser Asp Met Asp

1 5 10 15

Leu Gly Ala Arg Arg Tyr Ala Thr Arg Thr His Arg Ala Pro Pro Arg

20 25 30

Val Leu Lys Ala Pro Leu Pro

35

64

44

Artificial

5PAX12 44 mer fragment L-form

64

Arg Gly Trp Lys Cys Glu Gly Ser Gln Ala Ala Tyr Gly Asp Lys Asp

1 5 10 15

Ile Gly Arg Ser Arg Gly Cys Gly Ser Ile Thr Lys Asn Asn Thr Asn

20 25 30

His Ala His Pro Ser His Gly Ala Val Ala Lys Ile

35 40

65

39

Artificial

HAX9 39 mer fragment L-form

65

Ser Arg Glu Glu Ala Asn Trp Asp Gly Tyr Lys Arg Glu Met Ser His

1 5 10 15

Arg Ser Arg Phe Trp Asp Ala Thr His Leu Ser Arg Pro Arg Arg Pro

20 25 30

Ala Asn Ser Gly Asp Pro Asn

35

66

44

Artificial

HAX35 44 mer fragment L-form

66

Glu Trp Tyr Ser Trp Lys Arg Ser Ser Lys Ser Thr Gly Leu Gly Asp

1 5 10 15

Thr Ala Thr Arg Glu Gly Cys Gly Pro Ser Gln Ser Asp Gly Cys Pro

20 25 30

Tyr Asn Gly Arg Leu Thr Thr Val Lys Pro Arg Lys

35 40

67

44

Artificial

HAX40 44 mer fragment L-form

67

Arg Glu Phe Ala Glu Arg Arg Leu Trp Gly Cys Asp Asp Leu Ser Trp

1 5 10 15

Arg Leu Asp Ala Glu Gly Cys Gly Pro Thr Pro Ser Asn Arg Ala Val

20 25 30

Lys His Arg Lys Pro Arg Pro Arg Ser Pro Ala Leu

35 40

68

44

Artificial

HAX42 44 mer fragment L-form

68

Ser Asp His Ala Leu Gly Thr Asn Leu Arg Ser Asp Asn Ala Lys Glu

1 5 10 15

Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly Asn Ser Thr Gly Arg Lys

20 25 30

Val Phe Asn Arg Arg Arg Pro Ser Ala Ile Pro Thr

35 40

69

44

Artificial

HCA3 44 mer fragment L-form

69

Arg His Ile Ser Glu Tyr Ser Phe Ala Asn Ser His Leu Met Gly Gly

1 5 10 15

Glu Ser Lys Arg Lys Gly Cys Gly Ile Asn Gly Ser Phe Ser Pro Thr

20 25 30

Cys Pro Arg Ser Pro Thr Pro Ala Phe Arg Arg Thr

35 40

70

38

Artificial

H40 38 mer fragment L-form

70

Ser Arg Glu Ser Gly Met Trp Gly Ser Trp Trp Arg Gly His Arg Leu

1 5 10 15

Asn Ser Thr Gly Gly Asn Ala Asn Met Asn Ala Ser Leu Pro Pro Asp

20 25 30

Pro Pro Val Ser Thr Pro

35

71

39

Artificial

PAX2 39 mer fragment L-form

71

Ser Thr Pro Pro Ser Arg Glu Ala Tyr Ser Arg Pro Tyr Ser Val Asp

1 5 10 15

Ser Asp Ser Asp Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu

20 25 30

Arg Thr Arg Ser Arg Pro Asn

35

72

11

Artificial

binding 11 mer fragment L-form

72

Xaa Thr Xaa Xaa Ser Xaa Xaa Xaa Asn Xaa Arg

1 5 10

73

8

Artificial

binding 8 mer fragment L-form

73

Asp Xaa Asp Xaa Arg Arg Xaa Xaa

1 5

74

10

Artificial

binding 10 mer fragment L-form

74

Val Arg Ser Gly Cys Gly Xaa Xaa Ser Ser

1 5 10

75

11

Artificial

binding 11 mer fragment L-form

75

Asn Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg

1 5 10

76

11

Artificial

binding 11 mer fragment L-form

76

Ser Thr Lys Arg Ser Leu Ile Tyr Asn His Arg

1 5 10

77

10

Artificial

binding 10 mer fragment L-form

77

Ser Thr Gly Arg Lys Val Phe Asn Arg Arg

1 5 10

78

11

Artificial

binding 11 mer fragment L-form

78

Thr Asn Ala Lys His Ser Ser His Asn Arg Arg

1 5 10

79

8

Artificial

binding 8 mer fragment L-form

79

Asp Ser Asp Val Arg Arg Pro Trp

1 5

80

8

Artificial

binding 8 mer fragment L-form

80

Ala Ala Asp Gln Arg Arg Gly Trp

1 5

81

8

Artificial

binding 8 mer fragment L-form

81

Asp Gly Arg Gly Gly Arg Ser Tyr

1 5

82

4

Artificial

binding 4 mer fragment L-form

82

Arg Val Arg Ser

1

83

12

Artificial

binding 12 mer fragment L-form

83

Ser Val Arg Ser Gly Cys Gly Phe Arg Gly Ser Ser

1 5 10

84

11

Artificial

binding 11 mer fragment L-form

84

Ser Val Arg Gly Gly Cys Gly Ala His Ser Ser

1 5 10