Compounds having affinity for the granulocyte-colony stimulating factor receptor (G-CSFR) and associated uses

TECHNICAL FIELD

The present invention relates generally to novel compounds that have affinity for the granulocyte-colony stimulating factor receptor (G-CSFR). More particularly, the invention relates to such compounds which act as G-CSF mimetics by activating or inactivating the G-CSFR, or by affecting ligand binding to G-CSFR. The invention additionally relates to methods of using the novel compounds and pharmaceutical compositions containing a compound of the invention as the active agent. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides G-CSF mimetics for use in the treatment of human disease.

BACKGROUND

Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that specifically stimulates proliferation and differentiation of cells of the neutrophilic lineage.

G-CSF is a cytokine that binds to and activates the granulocyte-colony stimulating factor receptor (G-CSFR). G-CSFR is expressed on the surface of mature neutrophils and cells committed to the neutrophilic lineage, with receptor density varying from 190 to more than 1400 sites per cell. The receptor is a member of the cytokine receptor superfamily; it contains a cytokine receptor-homologous domain responsible for G-CSF binding, an immunoglobulin-like domain, three fibronectin type III domains, a transmembrane region, and an intracellular domain. The observed affinity of G-CSF for its receptor is about 100 pM.

The complete G-CSF protein has become an important therapeutic agent in clinical indications involving depressed neutrophil counts. Such indications include chemotherapy-induced neutropenia, AIDS and community acquired pneumonia. Furthermore, G-CSF antagonists may be useful in the treatment of some diseases caused by an inappropriate or undesirable activation of G-CSFR.

There remains a need, however, for compounds that bind specifically to G-CSFR, both for studies of the important biological activities mediated by the receptor and for treatment of diseases, disorders and conditions that would benefit from activating or inactivating G-CSFR. The present invention provides such compounds, and also provides pharmaceutical compositions and methods for using the compounds as therapeutic agents.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds comprising a peptide chain that binds to G-CSFR. In one aspect, the peptide chain is approximately 10 to 40 amino acids in length and contains a sequence of amino acids of formula (I)

CX

1

X

2

X

3

X

4

X

5

X

6

X

7

X

8

C (SEQ ID NO: 1) (I)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

1

is A, N, S, F, D, G, L, T, E, V, P, Q, H, M or K; X

2

is M, G, R, H, D, I, V, A, S, E, N, F, Y, P, C, W or T; X

3

is E, V, W, F, M, A, N, S, L, T, Y, G or P; X

4

is V, I, G, Q, W, M, T, Y, L, P, D, C, E or A; X

5

is M, E, W, L, P, N, I, T, V, F, Y, Q, S, R, W, G, H or D; X

6

is H, A, W, Y, V, F, Q, M, N, E, S, D, P or G; X

7

is M, F, Y, V, N, L, H, D, S, W, G, Q, C or T; and X

8

is C, Y, R, I, K, W, L, E, M, H, A, T, F, D, P, G or Q.

In another aspect, the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (II)

X

I

1

X

I

2

X

I

3

SGWVWX

I

4

(SEQ ID NO: 2) (II)

wherein each amino acid is indicated by the standard one-letter abbreviation, and wherein X

I

1

is S, Q, R, L or Y; X

I

2

is N, S, T, A or D; X

I

3

is E, D or N; and X

I

4

is L V, T, P or H.

In another aspect, the peptide chain is 6 to 40 amino acids in length and contains a sequence of amino acids of formula (III)

ERX

II

1

X

II

2

X

II

3

C (SEQ ID NO: 3) (III)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

II

1

is D, L, S, G, E, A, K or Y; X

II

2

is W, Y, F, L or V; and X

II

3

is F, G, M or L.

In still another aspect, the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (IV)

X

III

1

MVYX

III

2

X

III

3

PX

III

4

W (SEQ ID NO: 4) (IV)

wherein each amino acid in indicated by standard one-letter abbreviation, and wherein X

II

1

is D or E; X

III

2

is A or T; X

III

3

is Y or V; and X

III

4

is P or Y.

In an additional aspect, the invention provides compounds comprising a peptide chain approximately 12 to 40 amino acids in length and contains a sequence of amino acids of formula (V)

CX

IV

1

X

IV

2

X

IV

3

X

IV

4

X

IV

5

X

IV

6

X

IV

7

X

IV

8

X

IV

9

X

IV

10

C (SEQ ID NO: 5) (V)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

IV

1

is E, G, P, N, R, T, W, S, L, H, A, Q or Y; X

IV

2

is S, T, E, A, D, G, W, P, L, N, V, Y, R or M; X

IV

3

is R, Y, V, Q, E, T, L, P, S, K, M, A or W; X

IV

4

is L, M, G, F, W, R, S, V, P, A, D, C or T; X

IV

5

is V, T, A, R, S, L, W, C, I, E, P, H, F, D or Q; X

IV

6

is E, Y, G, T, Q, M, S, N, A or P; X

IV

7

is C, V, D, G, L, W, E, V, I, S, M or A; X

IV

8

is S, Y, A, W, P, V, L, Q, G, K, F, I, E or D; X

IV

9

is R, W, M, D, H, V, G, A, Q, L, S, E or Y; X

IV

10

is M, L, I, S, V, P, W, F, T, Y, R, or Q.

In another aspect the peptide chain is approximately 9 to 40 amino acids in length and contains a sequence of amino acids of formula (VI)

X

V

1

X

V

2

X

V

3

X

V

4

X

V

5

X

V

6

CX

V

7

X

V

8

(SEQ ID NO: 6) (VI)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

V

1

is E, C, Q, V, or Y; X

V

2

is E, A, L, M, S, W, or Q; X

V

3

is K, R or T; X

V

4

is L, A, or V; X

V

5

is R, A, M, H, E, V, L, G, D, Q, or S; X

V

6

is E or V; X

V

7

is A or G; X

V

8

is R H, G or L.

In a further aspect, the peptide chain is approximately 10 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (VII)

X

VI

1

X

VI

2

X

VI

3

X

VI

4

X

VI

5

EX

VI

6

X

VI

7

X

VI

8

X

VI

9

(SEQ ID NO: 7) (VII)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

VI

5

is A, E or G; X

VI

2

is E, H or D; X

VI

3

is R or G; X

VI

4

is K, Y, M, N, Q, R, D, I, S or E; X

VI

5

is A, S or P; X

VI

6

is E, D, T, Q, K or A: X

VI

7

is R, W, K, L, S, A or Q; X

VI

8

is R or E; and X

VI

9

is W, G, or R.

In a final aspect, the invention also provides peptides that, while not necessarily corresponding to one of the above-defined formulas, bind to G-CSFR.

In some contexts, the compounds of the invention are preferably in the form of a dimer. It is also preferred, in some contexts, that the compounds of the invention include a peptide wherein the N-terminus of the peptide is coupled to a polyethylene glycol molecule. In some contexts, it is preferred that the compounds of the invention include a peptide wherein the N-terminus of the peptide is acetylated. In addition, it is preferred, in some contexts, that the compounds of the invention include a peptide wherein the C-terminus of the peptide is amidated.

The invention also provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, as well as a method for treating a patient who would benefit from a G-CSFR modulator, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A

,

1

B,

1

C,

1

D,

1

E,

1

F,

1

G,

1

H,

1

I,

1

J and

1

K provide the sequences of representative peptide chains contained within the compounds of the invention.

FIGS. 2

,

3

,

4

,

5

,

6

,

7

,

8

,

9

A,

9

B

10

A,

10

B and

11

are graphs showing the results of various assays described in Examples.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and Overview

It is to be understood that unless otherwise indicated, this invention is not limited to specific peptide sequences, molecular structures, pharmaceutical compositions, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a novel compound” in a pharmaceutical composition means that more than one of the novel compounds can be present in the composition, reference to “a pharmaceutically acceptable carrier” includes combinations of such carriers, and the like.

In this specification and in the claims that follow, reference will be made to a number of terms which shall be defined to have the following meanings:

Amino acid residues in peptides are abbreviated as follows: Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is lie or I; Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gln or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Glu or E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; and Glycine is Gly or G. In addition, “1-Nal” is used to refer to 1-naphthylalanine, the “2-Nal” is used to refer to 2-naphthylalanine.

Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α,α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for compounds of the present invention. Examples of unconventional amino acids include: β-alanine, 1-naphthylalanine, 2-naphthylalanine, 3-pyridylalanine, 4-hydroxyproline, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, nor-leucine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).

“Peptide” or “polypeptide” refers to a polymer in which the monomers are alpha amino acids joined together through amide bonds. Peptides are two or often more amino acid monomers long. One or more of the peptide chains disclosed herein may appear in the compounds of the present. It is also contemplated that the peptide chains disclosed herein represent only a portion of the overall peptide included in the compound.

The term “dimer” as in a peptide “dimer” refers to a compound in which two peptide chains are linked; generally, although not necessarily, the two peptide chains will be identical and are linked through a linking moiety covalently bound to the carboxyl terminus of each chain.

The term “agonist” is used herein to refer to a ligand that binds to a receptor and activates the receptor.

The term “antagonist” is used herein to refer to a ligand that binds to a receptor without activating the receptor. Antagonists are either competitive antagonists or noncompetitive antagonists. A “competitive antagonist” blocks the receptor site that is specific for the agonist. A “noncompetitive antagonist” inactivates or otherwise affects the functioning of the receptor by interacting with a site other than the agonist binding site.

The term “modulator” as in a “G-CSFR-modulator” refers to a compound that is either an agonist or antagonist of the G-CSFR.

“Pharmaceutically or therapeutically effective dose or amount” refers to a dosage level sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. Preferably, this dose or amount will be sufficient to either at least partially activate or at least partially inactivate G-CSFR and, thus, alleviate the symptoms associated with an undesired neutrophil count in vivo.

An “optimal neutrophil count” refers to a quantity of neutrophils in a patient that is determined by a clinician to be optimal for that patient in light of the patient's disease state, condition, etc.

An “undesired neutrophil count” refers to a quantity of neutrophils in a patient that is determined by a clinician to be not optimal for that patient in light of the patient's disease state, condition, etc. Thus, an undesired neutrophil count may be depressed, elevated or even equal to the expected neutrophil count so long as the clinician determines that the actual count is not optimal for the patient. The compounds of the present invention are intended to, inter alia, provide the clinician with compounds that, when administered to a patient, bring that patient's neutrophil count closer to an optimal neutrophil count.

The term “treat” as in “treat a disease” is intended to include any means of treating a disease in a mammal, including (1) preventing the disease, i.e., avoiding any clinical symptoms of the disease, (2) inhibiting the disease, that is, arresting the development or progression of clinical symptoms, and/or (3) relieving the disease, i.e., causing regression of clinical symptoms.

“Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

By “pharmaceutically acceptable carrier” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

II. The Compounds

A. Compounds of Formula (I):

In a first embodiment, the invention provides compounds comprising a peptide chain that binds to G-CSFR, wherein the compounds comprise a peptide chain approximately 10 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (I)

CX

1

X

2

X

3

X

4

X

5

X

6

X

7

X

8

C (SEQ ID NO: 1) (I)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

1

is A, N, S, F, D, G, L, T, E, V, P, Q, H, M or K; X

2

is M, G, R, H, D, I, V, A, S, E, N, F, Y, P, C, W or T; X

3

is E, V, W, F, M, A, N, S, L, T, Y, G or P; X

4

is V, I, G, Q, W, M, T, Y, L, P, D, C, E or A; X

5

is M, E, W, L, P, N, I, T, V, F, Y, Q, S, R, W, G, H or D; X

6

is H, A, W, Y, V, F, Q, M, N, E, S, D, P or G; X

7

is M, F, Y, V, N, L, H, D, S, W, G, Q, C or T; and X

8

is C, Y, R, I, K, W, L, E, M, H, A, T, F, D, P, G or Q.

Preferably X

1

is D or P; X

2

is D or P; X

3

is E or W; X

4

is V, I or Y; X

5

is M or L; X

6

is W, Y or F; X

7

is M, Y or D; and X

8

is C or M. Examples of particularly preferred sequences satisfying formula (I) include, but are not limited to, the following:

CAGEVMHMCC (SEQ ID NO: 8);

CNREIEAMCC (SEQ ID NO: 9);

CADEVMHFCC (SEQ ID NO: 10);

CNREIMWMCC (SEQ ID NO: 11);

CSHEVWWYCC (SEQ ID NO: 12);

CSREVLYYCC (SEQ ID NO: 13);

CFIEGPWVCC (SEQ ID NO: 14);

CFVEGNWYCC (SEQ ID NO: 15);

CAAEVMVNCC (SEQ ID NO: 16);

CSDEVIFYCC (SEQ ID NO: 17);

CDREIMWFCC (SEQ ID NO: 18);

CAHEVMWMCC (SEQ ID NO: 19);

CGSEVTFMCC (SEQ ID NO: 20);

CLEEIMWLCC (SEQ ID NO: 21);

CAREVLAMCC (SEQ ID NO: 22);

CSVEVMQMCC (SEQ ID NO: 23);

CTNVQLMHYC (SEQ ID NO: 24);

CDVWQLFDRC (SEQ ID NO: 25);

CSFVQLNSIC (SEQ ID NO: 26);

CDYWQWFDKC (SEQ ID NO: 27);

CESFWVELWC (SEQ ID NO: 28);

CVPWMFYDLC (SEQ ID NO: 29);

CDPWMFYDLC (SEQ ID NO: 30);

CDPWVLFDEC (SEQ ID NO: 31);

CDHWTYFDMC (SEQ ID NO: 32);

CVVWTLYDKC (SEQ ID NO: 33);

CPDWYQSYMC (SEQ ID NO: 34);

CPDWYSYYMC (SEQ ID NO: 35);

CPEWYTDVMC (SEQ ID NO: 36);

CPDWYLDYMC (SEQ ID NO: 37);

CPEWYLDYMC (SEQ ID NO: 38);

CPDWYLPYMC (SEQ ID NO: 39);

CPEWYLPYMC (SEQ ID NO: 40);

CQDWWVELWC (SEQ ID NO: 41);

CPDWYLPWMC (SEQ ID NO: 42);

CACMLRVVHC (SEQ ID NO: 43);

CQRAGYMLAC (SEQ ID NO: 44);

CHANPVWGEC (SEQ ID NO: 45);

CFWSDWGQTC (SEQ ID NO: 46);

CPHWTSYYMC (SEQ ID NO: 47);

CETLCGACFC (SEQ ID NO: 48);

CATTINDTLC (SEQ ID NO: 49);

CLNYPHPVFC (SEQ ID NO: 50);

CMDGEMAVDC (SEQ ID NO: 51);

CNMGWMSWPC (SEQ ID NO: 52)

CETYADWLGC (SEQ ID NO: 53);

CDPWMFFDMC (SEQ ID NO: 54);

CDPWIWYDLC (SEQ ID NO: 55);

CDPWIMYDRC (SEQ ID NO: 56);

CDPWVFFDIC (SEQ ID NO: 57);

CDPWTYYDLC (SEQ ID NO: 58);

CDPWIFYDRC (SEQ ID NO: 59);

CDPWLFYDLC (SEQ ID NO: 60);

CDPWVWYDLC (SEQ ID NO: 61);

CDPWIFFDRC (SEQ ID NO: 62);

CDPWMFFDQC (SEQ ID NO: 63);

CDPWLWYDRC (SEQ ID NO: 64);

CDVWVWYDQC (SEQ ID NO: 65);

CDPWIYYDLC (SEQ ID NO: 66);

CVPWTLFDLC (SEQ ID NO: 67);

CPAWYLEYMC (SEQ ID NO: 68);

CPDWYLEYMC (SEQ ID NO: 69);

CKYWQWFDKC (SEQ ID NO: 70); and

CDHWMWYDKC (SEQ ID NO: 71).

Other preferred formula (I) sequences include, but are not limited to the following:

GCNREIEAMCCG (SEQ ID NO: 72);

GCPEWYTDVMCG (SEQ ID NO: 73);

NWYCMDGEMAVDCEAT (SEQ ID NO: 74);

WQSCNMGWMSWPCYFV (SEQ ID NO: 75);

HELCETYADWLGCVEW (SEQ ID NO: 76);

PCDPWMFFDMCERW (SEQ ID NO: 77);

LRGCDPWIWYDLCPAV (SEQ ID NO: 78);

GYLCDPWIFYDRCLGF (SEQ ID NO: 79);

RFACDPWVFFDICGYW (SEQ ID NO: 80);

GYWCDPWTYYDLCLTA (SEQ ID NO: 81);

MWTCDPWIFYDRCFLN (SEQ ID NO: 82);

GSSCDPWLFYDLCLLD (SEQ ID NO: 83);

GGGCDPWVWYDLCWCD (SEQ ID NO: 84);

YTSCDPWIFFDRCMSV (SEQ ID NO: 85);

DPYCDPWMFFDQCAYL (SEQ ID NO: 86);

REFCDPWLWYDRCL (SEQ ID NO: 87);

NTGCDVWVWYDQCFAM (SEQ ID NO: 88);

LVFCDPWIYYDLCMDT (SEQ ID NO: 89);

GCSFVQLNSICG (SEQ ID NO: 90);

GCPAWYLEYMCG (SEQ ID NO: 91);

GCPDWYLEYMCG (SEQ ID NO: 92);

GCKYWQWFDKCG (SEQ ID NO: 93); and

GCDHWMWYDKCG (SEQ ID NO: 94).

B. Compounds of Formula (II):

In another aspect, compounds are provided comprising a peptide chain approximately 9 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (II)

X

I

1

X

I

2

X

I

3

SGWVWX

I

4

(SEQ ID NO: 2) (II)

wherein each amino acid is indicated by the standard one-letter abbreviation, and wherein X

I

1

is S, Q, R, L or Y; X

I

2

is N, S, T, A or D; X

I

3

is E, D or N; and X

I

4

is L V, T, P or H.

Preferably X

I

1

is S or Q; X

I

2

is S; X

I

3

is N; and X

I

4

is V.

Examples of particularly preferred sequences satisfying formula (II) include, but are not limited to, the following:

SNESGWVWL (SEQ ID NO: 95);

QSNSGWVWV (SEQ ID NO: 96);

RTESGWVWT (SEQ ID NO: 97);

RANSGWVWV (SEQ ID NO: 98);

YDNSGWVWH (SEQ ID NO: 99); and

LSDSGWVWVP (SEQ ID NO: 100).

Other preferred formula (II) sequences include, but are not limited to, the following:

EQSNSGWVWVGGGGC (SEQ ID NO: 101);

CEQSNSGWVWV (SEQ ID NO: 102);

EQSNSGWVWVGGGGCKKK (SEQ ID NO: 103);

EQSNSGWVWVGKKKC (SEQ ID NO: 104);

EQSNSGWVWVGKKK (SEQ ID NO: 105);

KKKEQSNSGWVWV (SEQ ID NO: 106);

EQSNSGWVWVGKKKSKKK (SEQ ID NO: 107);

EQSNSGWVWVGGCKKK (SEQ ID NO: 108);

EQSNSGWVWVGGGGGGCKKK (SEQ ID NO: 109);

SNESGWVWLP (SEQ ID NO: 110);

EQSNSGWVWV (SEQ ID NO: 111);

SRTESGWVWT (SEQ ID NO: 112);

QRANSGWVWV (SEQ ID NO: 113);

DYDNSGWVWH (SEQ ID NO: 114);

EQSNSGWVWVGKKKK (SEQ ID NO: 115);

EQSNSGWVWVGGGGSKKK (SEQ ID NO: 116);

EQSNSGWVWVGGGGS (SEQ ID NO: 117);

EQSNSGWVWVGGGGSEQSNSGWVWVGGGGS (SEQ ID NO: 118);

RYQSFELSDSGWVWVPVARH (SEQ ID NO: 119); and

EQSNSGWVWVGGGGCKKKC (SEQ ID NO: 492).

C. Compounds of Formula (III):

In another aspect, the invention provides compounds comprising a peptide chain approximately 6 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (III)

ERX

II

1

X

II

2

X

II

3

C (SEQ ID NO: 3) (III)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

II

1

is D, L, S,G, E, A, K or Y; X

II

2

is W, Y, F, L or V; and X

II

3

is F, G, M or L.

Preferably, X

II

1

is D or L; X

II

2

is W; and X

II

3

is F.

Examples of particularly preferred sequences satisfying formula (III) include, but are not limited to, the following:

ERDWFC (SEQ ID NO: 120);

ERDWGC (SEQ ID NO: 121);

ERLWFC (SEQ ID NO: 122);

ERSYFC (SEQ ID NO: 123);

ERGWFC (SEQ ID NO: 124);

EREWFC (SEQ ID NO: 125);

ERAWFC (SEQ ID NO: 126);

ERLYFC (SEQ ID NO: 127);

ERYFMC (SEQ ID NO: 128);

ERLFLC (SEQ ID NO: 129);

ERALMC (SEQ ID NO: 130);

ERDVMC (SEQ ID NO: 131); and

ERKWFC (SEQ ID NO: 132).

Particulary preferred compounds are of the formula:

ETWGERDWFC (SEQ ID NO: 133);

ETWGERDWGC (SEQ ID NO: 134);

STAERLWFCG (SEQ ID NO: 135);

YETAERSYFC (SEQ ID NO: 136);

ADNAERGWFC (SEQ ID NO: 137);

QSNSEREWFC (SEQ ID NO: 138);

STSERAWFCG (SEQ ID NO: 139);

ASWSERGWFC (SEQ ID NO: 140);

ELSSEREWFC (SEQ ID NO: 141);

DMQGERGWFC (SEQ ID NO: 142);

SSSERAWFCG (SEQ ID NO: 143);

GNMRERLYFC (SEQ ID NO: 144);

QPNRERYFMC (SEQ ID NO: 145);

SVTRERLFLC (SEQ ID NO: 146);

IPLSERALMCSSWNC (SEQ ID NO: 147);

WARSERDVMCLSYVC (SEQ ID NO: 148);

QSNSEREWFCG (SEQ ID NO: 149);

QSNSEREWFCGGGGS (SEQ ID NO: 150);

NLEEALAQERLWFCRSGNC (SEQ ID NO: 151); and

NLESYEMEERKWFCKMFSC (SEQ ID NO: 152).

D. Compounds of Formula (IV):

In another aspect, compounds are provided comprising a peptide chain approximately 9 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (IV):

X

III

1

MVYX

III

2

X

III

3

PX

III

4

W (SEQ ID NO: 4) (IV)

wherein each amino acid in indicated by standard one-letter abbreviation, and wherein X

III

1

is D or E; X

III

2

is A or T; X

III

3

is Y or V; and X

III

4

is P or Y.

Examples of particularly preferred sequences satisfying formula (IV) include, but are not limited to, the following:

DMVYAYPPW (SEQ ID NO: 153); and

EMVYTVPYW (SEQ ID NO: 154).

Other preferred formula (IV) sequences include, but are not limited to, the following:

DMVYAYPPWS (SEQ ID NO: 155); and

DEMVYTVPYW (SEQ ID NO: 156).

E. Compounds of Formula (V):

In another aspect, compounds are provided comprising a peptide chain approximately 12 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (V):

CX

IV

1

X

IV

2

X

IV

3

X

IV

4

X

IV

5

X

IV

6

X

IV

7

X

IV

8

X

IV

9

X

IV

10

C (SEQ ID NO: 5) (V)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

IV

1

is E, G, P, N, R, T, W, S, L, H, A, Q or Y; X

IV

2

is S, T, E, A, D, G, W, P, L, N, V, Y, R or M; X

IV

3

is R, Y, V, Q, E, T, L, P, S, K, M, A or W; X

IV

4

is L, M, G, F, W, R, S, V, P, A, D, C or T; X

IV

5

is V, T, A, R, S, L, W, C, I, E, P, H, F, D or Q; X

IV

6

is E, Y, G, T, Q, M, S, N, A or P; X

IV

7

is C, V, D, G, L, W, E, V, I, S, M or A; X

IV

8

is S, Y, A, W, P, V, L, Q, G, K, F, I, E or D; X

IV

9

is R, W, M, D, H, V, G, A, Q, L, S, E or Y; X

IV

10

is M, L, I, S, V, P, W, F, T, Y, R, or Q.

Preferably X

IV

1

is E; X

IV

2

is S or A; X

IV

3

is R; X

IV

4

is L; X

IV

5

is V or S; X

IV

6

is E; X

IV

7

is C; X

IV

8

is S; X

IV

9

is R; and X

IV

10

is L.

Examples of particularly preferred sequences satisfying formula (V) include, but are not limited to, the following:

CESRLVECSRMC (SEQ ID NO: 157);

CETYMTYVYWLC (SEQ ID NO: 158);

CGERLAECARLC (SEQ ID NO: 159);

CESRLRECSMLC (SEQ ID NO: 160);

CEARLSECSRIC (SEQ ID NO: 161);

CPARLLECSRMC (SEQ ID NO: 162);

CESVGVGDWWSC (SEQ ID NO: 163);

CEDRLVEGPWVC (SEQ ID NO: 164);

CNDQFRTCVDVC (SEQ ID NO: 165);

CRGEWWELYHPC (SEQ ID NO: 166);

CEDTRTGWAWSC (SEQ ID NO: 167);

CTWLSSGELVWC (SEQ ID NO: 168);

CWPPVCEVSGIC (SEQ ID NO: 169);

CSLSPIQLQHLC (SEQ ID NO: 170);

CLARLEECSRFC (SEQ ID NO: 171);

CHNSSPMVGVTC (SEQ ID NO: 172);

CHVSPVQIKALC (SEQ ID NO: 173);

CAAPATSWFQYC (SEQ ID NO: 174);

CASKLHECSLRC (SEQ ID NO: 175);

CEPMDSNGIVQC (SEQ ID NO: 176);

CQYASAADEQRC (SEQ ID NO: 177);

CEYWDEPSLSWC (SEQ ID NO: 178);

CERECFQMLERC (SEQ ID NO: 179);

CGMSTDELDEIC (SEQ ID NO: 180);

CYVSPSTGLYSC (SEQ ID NO: 181);

CEARLVECSRLC (SEQ ID NO: 182);

CESRLSECSRMC (SEQ ID NO: 183);

CELKLQECARRC (SEQ ID NO: 184);

CELKLQEAARRC (SEQ ID NO: 185); and

CLERLEECSRFC (SEQ ID NO: 186).

Other preferred formula (V) sequences include but are not limited to, the following:

GGCESRLVECSRMC (SEQ ID NO: 187);

GGCETYMTYVYWLC (SEQ ID NO: 188);

EWLCESVGVGDWWSC (SEQ ID NO: 189);

YHPCEDRLVEGPWVCCRS (SEQ ID NO: 190);

WLLCNDQFRTCVDVCDNV (SEQ ID NO: 191);

IAECRGEWWELYHPCLAA (SEQ ID NO: 192);

TWYCEDTRTGWAWSCLEL (SEQ ID NO: 193);

QLDCTWLSSGELVWCSDW (SEQ ID NO: 194);

QFDCTWLSSGELVWCSDW (SEQ ID NO: 195);

CWPPVCEVSGICS (SEQ ID NO: 196);

CGCSLSPIQLQHLC (SEQ ID NO: 197);

CGCHVSPVQIKALC (SEQ ID NO: 198);

GCHVSPVQIKALC (SEQ ID NO: 199);

GTSCAAPATSWFQYCVLP (SEQ ID NO: 200);

RMDCASKLHECSLRCAYA (SEQ ID NO: 201);

GVVCEPMDSNGIVQCSMR (SEQ ID NO: 202);

IDVCQYASAADEQRCLRI (SEQ ID NO: 203);

NVLCEYWDEPSLSWCLSS (SEQ ID NO: 204);

CQCERECFQMLERC (SEQ ID NO: 205);

FCSCGMSTDELDEICAIW (SEQ ID NO: 206);

EEVCYVSPSTGLYSCYDQ (SEQ ID NO: 207);

LLDICELKLQECARRCN (SEQ ID NO: 208);

GGGLLDICELKLQECARRCN (SEQ ID NO: 209);

GRTGGGLLDICELKLQECARRCN (SEQ ID NO: 210);

LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO: 211);

LLDICELKLQEAARRCN (SEQ ID NO: 212); and

KLLDICELKLQEAARRCN (SEQ ID NO: 213).

Particularly preferred formula (V) sequences are selected from the group consisting of:

LLDICELKLQECARRCN (SEQ ID NO: 208);

GGGLLDICELKLQECARRCN (SEQ ID NO: 209);

GRTGGGLLDICELKLQECARRCN (SEQ ID NO: 210);

LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO: 211);

LLDICELKLQEAARRCN (SEQ ID NO: 212); and

KLLDICELKLQEAARRCN (SEQ ID NO: 213).

F. Compounds of Formula (VI):

In another aspect, compounds are provided comprising a peptide chain approximately 9 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (VI):

X

V

1

X

V

2

X

V

3

X

V

4

X

V

5

X

V

6

CX

V

7

X

V

8

(SEQ ID NO: 6) (VI)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

V

1

is E, C, Q, V, or Y; X

V

2

is E, A, L, M, S, W, or Q; X

V

3

is K, R or T; X

V

4

is L, A, or V; X

V

5

is R, A, M, H, E, V, L, G, D, Q, or S; X

V

6

is E or V; X

V

7

is A or G; X

V

8

is R, H, G or L.

Preferably X

V

1

is E; X

V

2

is A or L; X

V

3

is K or R; X

V

4

is L; X

V

6

is E; X

V

7

is A; and X

V

8

is R.

Examples of particularly preferred sequences satisfying formula (VI) include, but are not limited to, the following:

EEKLRECAR (SEQ ID NO: 214);

EARLAECAR (SEQ ID NO: 215);

CMKLMECAR (SEQ ID NO: 216);

ELRLRECAH (SEQ ID NO: 217);

EAKLHECAR (SEQ ID NO: 218);

ELKLAECAR (SEQ ID NO: 219);

EARLEECAR (SEQ ID NO: 220);

EAKLRECAR (SEQ ID NO: 221);

ELRLAECAR (SEQ ID NO: 222);

ESRLAECAR (SEQ ID NO: 223);

EAKLVECAR (SEQ ID NO: 224);

ESRLRECAR (SEQ ID NO: 225);

EAKLAECAR (SEQ ID NO: 226);

QWRLEECAR (SEQ ID NO: 227);

QLRLEECAR (SEQ ID NO: 228);

ELRLEECAR (SEQ ID NO: 229);

EAKLLECAR (SEQ ID NO: 230);

EARAGVCAG (SEQ ID NO: 231);

EAKAGVCAG (SEQ ID NO: 232);

VARLEECAR (SEQ ID NO: 233);

ELKLDECAR (SEQ ID NO: 234);

EWRLQECAR (SEQ ID NO: 235);

EAKLSECAR (SEQ ID NO: 236);

EARLSECAR (SEQ ID NO: 237);

ELKLLECAR (SEQ ID NO: 238);

ELRLQECGR (SEQ ID NO: 239);

EQKLAECAR (SEQ ID NO: 240);

ELRLQECAR (SEQ ID NO: 241);

ELKLEECAR (SEQ ID NO: 242);

ESRLEECAR (SEQ ID NO: 243);

EATVQECAR (SEQ ID NO: 244);

ELKLQECAR (SEQ ID NO: 245);

YSRLEECGR (SEQ ID NO: 246);

ELRLRECAL (SEQ ID NO: 247);

EARLLECAR (SEQ ID NO: 248);

ESRLLECAR (SEQ ID NO: 249);

VLKLEECAR (SEQ ID NO: 250);

ESKLAECAR (SEQ ID NO: 251);

ESKLRECAR (SEQ ID NO: 252);

EYKLGECAR (SEQ ID NO: 253);

ESRLQECAR (SEQ ID NO: 254);

QARLAECAR (SEQ ID NO: 255);

ELKKQECAR (SEQ ID NO: 256);

ESRLSECAR (SEQ ID NO: 257);

EARLEECGR (SEQ ID NO: 258);

ESRLAECGR (SEQ ID NO: 259);

EWRLEECAR (SEQ ID NO: 260);

EARLSECGR (SEQ ID NO: 261);

AARLAECAR (SEQ ID NO: 262);

EWKLAECAR (SEQ ID NO: 263);

ESKLEECAR (SEQ ID NO: 264);

DVKLAECAR (SEQ ID NO: 265);

ELQLEECAR (SEQ ID NO: 266); and

EYKLASCAR (SEQ ID NO: 267).

Other preferred formula (VI) sequences include but are not limited to, the following:

RLSICEEKLRECARGC (SEQ ID NO: 268);

PLTTCEARLAECARQL (SEQ ID NO: 269);

LALCMKLMECARRY (SEQ ID NO: 270);

ELVMCELRLRECAHRA (SEQ ID NO: 271);

PLARCEAKLHECARQL (SEQ ID NO: 272);

LLSVCELKLAECARSK (SEQ ID NO: 273);

RLEWCEARLEECARRC (SEQ ID NO: 274);

RLRVVEAKLRECARGR (SEQ ID NO: 275);

CVAHLELRLAECARQI (SEQ ID NO: 276);

HLARCESRLAECARQL (SEQ ID NO: 277);

RLALLEAKLVECARRL (SEQ ID NO: 278);

DLFSLESRLRECARRV (SEQ ID NO: 279);

AVPVLEAKLAECARRF (SEQ ID NO: 280);

YLQQLQWRLEECARGM (SEQ ID NO: 281);

YLELCQLRLEECARQFN (SEQ ID NO: 282);

ELHICELRLEECARGR (SEQ ID NO: 283);

RVARCELRLAECARKS (SEQ ID NO: 284);

YLEVLESRLAECARWK (SEQ ID NO: 285);

EAKLLECARAR (SEQ ID NO: 286);

ELSLCEARAGVCAGSVTK (SEQ ID NO: 287);

ELSLCEAKAGVCAGSVTK (SEQ ID NO: 288);

ALWQCVARLEECARSR (SEQ ID NO: 289);

CLKSCELKLDECARRM (SEQ ID NO: 290);

ALQTCEWRLQECARSR (SEQ ID NO: 291);

YISQCEAKLAECARLY (SEQ ID NO: 292);

ELSSCEAKLSECARRW (SEQ ID NO: 293);

ELSSCEARLSECARRW (SEQ ID NO: 294);

QLLQCELKLLECARQG (SEQ ID NO: 295);

ELLRCEARLAECARGC (SEQ ID NO: 296);

QLRQCELRLQECGRHGN (SEQ ID NO: 297);

PLTSCEQKLAECARRF (SEQ ID NO: 298);

LLGMCELRLQECARAK (SEQ ID NO: 299);

ELSRCELKLEECARGM (SEQ ID NO: 300);

DCRPCESRLEECARRL (SEQ ID NO: 301);

RLSVCEARLEECARQL (SEQ ID NO: 302);

PLKMCEATVQECARLI (SEQ ID NO: 303);

LLLFCEARLSECARHV (SEQ ID NO: 304);

SLSMCEARLAECARLL (SEQ ID NO: 305);

PLFSCELKLQECARRCN (SEQ ID NO: 306);

SLERCYSRLEECGRRI (SEQ ID NO: 307);

PLTSCELRLRECALRSN (SEQ ID NO: 308);

KLAACELKLAECARRW (SEQ ID NO: 309);

KLAACELRLAECARRW (SEQ ID NO: 310);

ALTRCELRLAECARKI (SEQ ID NO: 311);

LLQQCELKLAECARSI (SEQ ID NO: 312);

QLWQCEARLLECARRS (SEQ ID NO: 313);

RLRLCESRLLECARSL (SEQ ID NO: 314);

QLETCVLKLEECARRCN (SEQ ID NO: 315);

ALSQCELRLAECARSVTK (SEQ ID NO: 316);

ELKLAECARRS (SEQ ID NO: 317);

ALSRCESKLAECARRQ (SEQ ID NO: 318);

LMSTCESKLRECARSL (SEQ ID NO: 319);

SLQRCEYKLGECARSL (SEQ ID NO: 320);

RLELLESRLQECARQLN (SEQ ID NO: 321);

QMEWCQARLAECARCCN (SEQ ID NO: 322);

PLFSCELKKQECARRCN (SEQ ID NO: 323);

LLDKCESRLSECARRL (SEQ ID NO: 324);

LLARCEARLEECGRQC (SEQ ID NO: 325);

DLLYCESRLAECGRM (SEQ ID NO: 326);

ALQMCEWRLEECARRL (SEQ ID NO: 327);

LLTMCEARLSECGRRL (SEQ ID NO: 328);

ALWRCESRLAECARRS (SEQ ID NO: 329);

LLATCAARLAECARQL (SEQID NO: 330);

LQTCEWKLAECARSN (SEQ ID NO: 331);

PLRSCESKLEECARQL (SEQ ID NO: 332);

CLRALDVKLAECARHL (SEQ ID NO: 333);

RLKTLELQLEECARRS (SEQ ID NO: 334);

KLRDVELKLAECARRS (SEQ ID NO: 335);

SLQRCEYKLASCARSL (SEQ ID NO: 336);

RLARCELRLAECARKS (SEQ ID NO: 337);

DLWYLESKLEECARRCN (SEQ ID NO: 338);

DLWYLESKLEECARRANG (SEQ ID NO: 339);

DLWYLESKLEECARRCNG (SEQ ID NO: 340);

KQRELELKLAECARRS (SEQ ID NO: 341);

QMQEWCARLAECARCCN (SEQ ID NO: 342); and

LLDICELKLQECARRAN (SEQ ID NO: 343).

A particularly preferred sequence of formula (VI) is:

LLDICELKLQECARRAN (SEQ ID NO: 343).

G. Compounds of Formula (VII):

In another aspect, the invention provides compounds comprising a peptide chain approximately 10 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids of formula (VII):

X

VI

1

X

VI

2

X

VI

3

X

VI

4

X

VI

5

EX

VI

6

X

VI

7

X

VI

8

X

VI

9

(SEQ ID NO: 7) (VII)

wherein each amino acid is indicated by standard one-letter abbreviation, and wherein X

VI

1

is A, E or G; X

VI

2

is E, H or D; X

VI

3

is R or G; X

VI

4

is K, Y, M, N, Q, R, D, I, S or E; X

VI

5

is A, S or P; X

VI

6

is E, D, T, Q, K or A: X

VI

7

is R, W, K, L, S, A or Q; X

VI

8

is R or E; and X

VI

9

is W, G, or R.

Preferably X

VI

1

is A; X

VI

2

is E; X

VI

3

is R; X

VI

5

is A; X

VI

6

is E; X

VI

7

is R; X

VI

8

is R; and X

VI

9

is W.

Examples of particularly preferred sequences satisfying formula (VII) include, but are not limited to, the following:

AERKAEERRW (SEQ ID NO: 344);

AERYAEEREG (SEQ ID NO: 345);

AERMAEERRW (SEQ ID NO: 346);

AERKAEERRR (SEQ ID NO: 347);

AHRNAEERRW (SEQ ID NO: 348);

AERKSEDWRW (SEQ ID NO: 349);

AERKAEEKRR (SEQ ID NO: 350);

AERQAETRRW (SEQ ID NO: 351);

AERNAEERRW (SEQ ID NO: 352);

AERQAEERRW (SEQ ID NO: 353);

AERRAEERRW (SEQ ID NO: 354);

AERDAEQRRW (SEQ ID NO: 355);

AERIAEERRW (SEQ ID NO: 356);

AERSAEERRW (SEQ ID NO: 357);

AERKAEELRW (SEQ ID NO: 358);

AERKAEESRW (SEQ ID NO: 359);

EERKAEERRW (SEQ ID NO: 360);

ADGKAEERRW (SEQ ID NO: 361);

ADGKAEELRW (SEQ ID NO: 362);

ADGMPEERRW (SEQ ID NO: 363);

ADGEAEKRRW (SEQ ID NO: 364);

ADGNAEERRW (SEQ ID NO: 365);

ADGEAEKARW (SEQ ID NO: 366);

AEGEAEKARW (SEQ ID NO: 367);

GERKAEERRW (SEQ ID NO: 368);

AEREAEERRW (SEQ ID NO: 369);

ADGEAEARRW (SEQ ID NO: 370);

ADGRAEEARW (SEQ ID NO: 371);

AEGRAEEARW (SEQ ID NO: 372);

AEREAEKARW (SEQ ID NO: 373);

AERKAEEQRW (SEQ ID NO: 374);

AERDAEKRRW (SEQ ID NO: 375); and

AEREAEKLRW (SEQ ID NO: 376).

Other preferred formula (VI) sequences include but are not limited to, the following:

MLAERKAEERRWFNTHGRE (SEQ ID NO: 377);

MLAERKAEERRWFNTHGREK (SEQ ID NO: 378);

GGGMLAERKAEERRWFNTHGRE (SEQ ID NO: 379);

CMLAERKAEERRWFNTHGRE (SEQ ID NO: 380);

CMLAERKAEERRWFNTHGREK (SEQ ID NO: 381);

MLAERYAEEREGFNMQWRE (SEQ ID NO: 382);

MLAERMAEERRWFRRMG (SEQ ID NO: 383);

IVAERKAEERRRLNTEGHE (SEQ ID NO: 384);

ILAHRNAEERRWFQKHGR (SEQ ID NO: 385);

MLAERKSEDWRWLKTHGRD (SEQ ID NO: 386);

MLAERKAEEKRRLKTQGRE (SEQ ID NO: 387);

ILAERQAETRRWMRNAGSVTK (SEQ ID NO: 388);

MLAERNAEERRWLKRQCG (SEQ ID NO: 389);

MLAERQAEERRWLKMHGGE (SEQ ID NO: 390);

MLAERRAEERRWLKTQGGD (SEQ ID NO: 391);

MLAERQAEERRWLKTQGRD (SEQ ID NO: 392);

MLAERKAEERRWFKTHGRE (SEQ ID NO: 393);

MLAERKAEERRWFNNQGRE (SEQ ID NO: 394);

MPAERDAEQRRWLKTHGRE (SEQ ID NO: 395);

ILAERIAEERRWLKTQGR (SEQ ID NO: 396);

MLAERKAEERRWLQTHGRE (SEQ ID NO: 397);

ILAERSAEERRWLKTQGRE (SEQ ID NO: 398);

LLAERKAEELRWLKTHGRE (SEQ ID NO: 399);

MLAERKAEERRWLQTHGRE (SEQ ID NO: 400);

MLAERNAEERRW (SEQ ID NO: 401);

MFAERKAEESRWLQSQGRE (SEQ ID NO: 402);

MLEERKAEERRWLKTHGR (SEQ ID NO: 403);

MLAERKAEERRWLKMQGRE (SEQ ID NO: 404);

MLAERNAEERRWFYTHGRE (SEQ ID NO: 405);

MLADGKAEERRWLKTHGLD (SEQ ID NO: 406);

MIADGKAEERRWLKTHGRD (SEQ ID NO: 407);

MLADGKAEELRWLKTQGSD (SEQ ID NO: 408);

MLAERNAEERRWLKTHGRD (SEQ ID NO: 409);

MLADGKAEELRWLKTQGRE (SEQ ID NO: 410);

ILADGKAEERRWLKTHGRD (SEQ ID NO: 411);

MLADGMPEERRWLQTHGRD (SEQ ID NO: 412);

MLADGEAEKRRWLNTHGRD (SEQ ID NO: 413);

MLADGNAEERRWLMTHGRD (SEQ ID NO: 414);

MLADGEAEKARWLKTQGRE (SEQ ID NO: 415);

MLAEGEAEKARWLKTQGRE (SEQ ID NO: 416);

MLADGKAEERRWLKTQGRE (SEQ ID NO: 417);

MLAERKAEERRWLSAHVRE (SEQ ID NO: 418);

LLGERKAEERRWYKTHARE (SEQ ID NO: 419);

MLAERKAEERRWLMTHGHD (SEQ ID NO: 420);

MLAERKAEERRWLKSQCLE (SEQ ID NO: 421);

LLAEREAEERRWFKTHGRE (SEQ ID NO: 422);

MLADGEAEARRWFNMHGRE (SEQ ID NO: 423);

MLADGRAEEARWLKTQGSE (SEQ ID NO: 424);

MLAEGRAEEARWLKTQGSE (SEQ ID NO: 425);

MLAEREAEKARWLKTQGRE (SEQ ID NO: 426);

MMAERKAEEQRWFDIHGRD (SEQ ID NO: 427);

LTAERDAEKRRWLLTHGGE (SEQ ID NO: 428);

MLAERQAEERRWLKSQRGE (SEQ ID NO: 429);

LLAERKAEERRWFATHGRD (SEQ ID NO: 430);

MLAEREAEKLRWLKSQERA (SEQ ID NO: 431);

MLAERKAEERRWLKTHGGE (SEQ ID NO: 432);

KGGGMLAERKAEERRWFNTHGRE (SEQ ID NO: 490); and

KSTGGLTAERDAEKRRWLLTHGGE (SEQ ID NO: 491).

H. Other Active Compounds

In another aspect of the invention, there are provided additional compounds comprising a peptide chain approximately 5 to 40 amino acids in length that binds to G-CSFR and contains a sequence of amino acids selected from the following compounds:

CTWTDLESVY (SEQ ID NO: 433);

HTTNEQFFMC (SEQ ID NO: 434);

DTWLELESRY (SEQ ID NO: 435);

HNSSPMVGVT(SEQ ID NO: 436);

DWQKTIPAYW (SEQ ID NO: 437);

RWGREGLVAALL (SEQ ID NO: 438);

WSGTRVWRCVVT (SEQ ID NO: 439);

MSLLSYLRS (SEQ ID NO: 440);

LDLLAI (SEQ ID NO: 441);

RIYGVK (SEQ ID NO: 442);

MIWHMFMSLLF (SEQ ID NO: 443);

FFWASWMHLLW (SEQ ID NO: 444);

FDDCWREREQFLFQAL (SEQ ID NO: 445);

CGRASECFRLLEM (SEQ ID NO: 446);

RECFQMLER (SEQ ID NO: 447);

CSIRWDFVPGYGLC (SEQ ID NO: 448);

WMQCWDSLSLCYDM (SEQ ID NO: 449);

ALLMCESKLAECARAR (SEQ ID NO: 450);

LAHCKKRKEECAAG (SEQ ID NO: 451);

SIDGVYLRTSRT (SEQ ID NO: 452);

SIDGVYLRTRSRTRY (SEQ ID NO: 453);

VRWLRGSTLRGLRDR (SEQ ID NO: 454);

DRGGGTVGVYWWESY (SEQ ID NO: 455);

VWGTVGTWLEY (SEQ ID NO: 456);

LMWVSAY (SEQ ID NO: 457);

RASDEYGALVRFCTNL (SEQ ID NO: 458);

NYWCDSNWVCEIA (SEQ ID NO: 459);

LAHCLLRLEECAAG (SEQ ID NO: 460);

LALCLARLRECAGG (SEQ ID NO: 461);

CESRLVECSRM (SEQ ID NO: 462);

LLDIAELKLQECARRCN (SEQ ID NO: 463);

KLLDIAELKLQECCARRCN (SEQ ID NO: 464);

CSTGGGLTAERDAEKRRWLLTHGGE (SEQ ID NO: 465)

LTAERDAEKRRWLLTHGGEGG (SEQ ID NO: 466);

LTAERDAEKRRWLLTHGGEGGK (SEQ ID NO: 467);

LTAERDAEKRRWLLTHGGEGGGGG (SEQ ID NO: 468);

LTAERDAEKRRWLLTHGGEGGGGGK (SEQ ID NO: 469);

ESGWVW (SEQ ID NO: 470);

NSGWVW (SEQ ID NO: 471);

SGWVW (SEQ ID NO: 472);

PLGKCEATCREMARYFN (SEQ ID NO: 473);

SLQRCEYKLASVRGLCN (SEQ ID NO: 474)

DLWYLESKLEEAARRCNG (SEQ ID NO: 475);

PYMGTRSRAKLLRQQ (SEQ ID NO: 476);

RNAGERRWFKTQGWY (SEQ ID NO: 477);

MLAERNADDRRWFNTHGRD (SEQ ID NO: 478);

MMADGRLRNSVGLILWCD (SEQ ID NO: 479);

MLADGRLRNVVG (SEQ ID NO: 480);

LLADVRRRNGVGLLRMGRD (SEQ ID NO: 481);

MLADGRLRNFGG (SEQ ID NO: 482);

TYMTYVYWLC (SEQ ID NO: 483);

RFGERWGL (SEQ ID NO: 484);

HWLWWGWNF (SEQ ID NO: 485);

RECFQMLERC (SEQ ID NO: 486);

ILAHRNAKERRWFQKHGR (SEQ ID NO: 487); and

CSTGGGLTAERDAEKRRWLLTHGGEK (SEQ ID NO: 489).

Particularly preferred sequences are selected from the group consisting of:

LLDIAELKLQECARRCN (SEQ ID NO: 463); and

KLLDIAELKLQECCARRCN (SEQ ID NO: 464).

I. Synthesis of the Peptides:

Standard solid phase peptide synthesis techniques are preferred for synthesis of the peptides of the present invention. Such techniques are described, for example, by Merrifield (1963)

J. Am. Chem. Soc

. 85:2149. As is well known in the art, solid phase synthesis using the Merrifield method involves successive coupling of α-amino protected amino acids to a growing support-bound peptide chain. After the initial coupling of a protected amino acid to a resin support (e.g., a polystyrene resin, a chloromethylated resin, a hydroxymethyl resin, a benzhydrylamine resin, or the like, depending on the chemistry used), the α-amino protecting group is removed by a choice of reagents, depending on the specific protecting group. Suitable α-amino protecting groups are those known to be useful in the art of stepwise synthesis of peptides. Included are acyl type protecting groups (e.g., formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g., benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g., t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl), alkyl type protecting groups (e.g., benzyl, triphenylmethyl), fluorenylmethyl oxycarbonyl (Fmoc), alloxycarbonyl (Alloc) and Dde. The side chain protecting groups (typically ethers, esters, trityl, and the like) remain intact during coupling; however, the side chain protecting group must be removable upon completion of the synthesis of the final peptide. Preferred side chain protecting groups, as will appreciated by those skilled in the art, will depend on the particular amino acid that is being protected as well as the overall chemistry used. After removal of the α-amino protecting group, the remaining protected amino acids are coupled stepwise in the desired order. Each protected amino acid is generally reacted in about a 3-fold excess using an appropriate carboxyl group activator such as 2-(1H-benzotriazol-1-yl)-1,1,3,3 tetramethyluronium hexafluorophosphate (HBTU) or dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride (CH

2

Cl

2

), N-methyl pyrrolidone, dimethyl formamide (DMF), or mixtures thereof.

Once the synthesis is complete, the compound is cleaved from the solid support by treatment with a reagent such as trifluoroacetic acid, preferably in combination with a scavenger such as ethanedithiol, P-mercaptoethanol or thioanisole. The cleavage reagent not only cleaves the peptide from the resin, but also cleaves all remaining side chain protecting groups.

These procedures can also be used to synthesize peptides containing amino acids other than the 20 naturally occurring, genetically encoded amino acids. For instance, naphthylalanine can be substituted for tryptophan, with 1-Nal or 2-Nal. Other synthetic amino acids that can be substituted into the peptides of the present invention include, but are not limited to, nor-leucine and 3-pyridylalanine.

III. Variation and Modification of the Compounds

A. Dimer Forms (With a Terminal Linking Moiety):

The compounds of the present invention may be in the form of a dimer, i.e., a compound comprised of two similar (but not necessarily identical) peptide sequences. Preferably, the dimer compounds of the invention have the structure of formula (VIII)

wherein R

1

, R

2

, n1, n2, n3, n4, x, y and Lk are defined as follows.

R

1

is a peptide chain that binds to G-CSFR and contains a sequence of amino acids of the present invention. R

2

is also a peptide chain that binds to G-CSFR and contains a sequence of amino acids of the present invention. As previously indicated, R

1

and R

2

can be the same or different. It is preferred, however, that R

1

and R

2

are the same.

βA is a β-alanine residue and may or may not be present, meaning that n1, n2, n3 and n4 are independently zero or 1.

Lk is a terminal linking moiety. If the dimer contains only one linking moiety, one of x and y is zero and the other is one. Alternatively, if the dimer contains two linking moieties, both x and y are one. Thus, x and y are independently zero or one with the proviso that the sum of x and y is either one or two.

The terminal linking moiety Lk can be any moiety recognized by those skilled in the art as suitable for joining the peptides of R

1

and R

2

. Lk is preferably although not necessarily selected from the group consisting of a disulfide bond, a carbonyl moiety and a C

1-12

linking moiety optionally terminated with one or two —NH— linkages and optionally substituted at one or more available carbon atoms with a lower alkyl substituent. Preferably, the terminal linking moiety comprises —NH—R

3

—NH— wherein R

3

is lower (C

1-6

) alkylene substituted with a functional group such as a carboxyl group or an amino group that enables coupling to another molecular moiety (e.g., as may be present on the surface of a solid support), and is optionally substituted with a lower alkyl group. Optimally, the linking moiety is a lysine residue or lysine amide, i.e., a lysine residue wherein the carboxyl group has been converted to an amide moiety —CONH

2

.

B. Disulfide Bonds:

When a pair of cysteine residues is present in a peptide of the invention, it is preferred that the pair form a disulfide bond linking these residues. The disulfide bond may be present within a single peptide chain forming an intramolecular disulfide bond. Alternatively, if the compound includes an additional cysteine-containing peptide chain, the disulfide bond may connect the two chains. In addition, where an additional pair of cysteine residues exists in the compound, more than one disulfide bond may be present.

Disulfide bond formation may be effected by techniques well known to those skilled in the art. One such technique involves employing a suitable oxidizing reagent such that a disulfide bond forms from the free thiols from a pair of cysteine residues. Undesired disulfide bond formation can be minimized, for example, by protecting the thiol groups of those cysteine residues not intended to form disulfide bonds and oxidizing the peptide before removal of any protecting groups. Preferred compounds having disulfide bonds include, by way of example, the following:

A particularly preferred compound having disulfide bonds includes

C. N-Terminal Modifications:

(i) Pegylated Compounds

The peptides and compounds of the invention can advantageously be modified with or covalently coupled to one or more of a variety of hydrophilic polymers. It has been found that when the peptide compounds are derivatized with a hydrophilic polymer, their solubility and circulation half-lives are increased and their immunogenicity is masked. Quite surprisingly, the foregoing can be accomplished with little, if any, diminishment in binding activity. Nonproteinaceous polymers suitable for use in accordance with the present invention include, but are not limited to, polyalkylethers as exemplified by polyethylene glycol and polypropylene glycol, polylactic acid, polyglycolic acid, polyoxyalkenes, polyvinylalcohol, polyvinylpyrrolidone, cellulose and cellulose derivatives, dextran and dextran derivatives, etc. Generally, such hydrophilic polymers have an average molecular weight ranging from about 500 to about 100,000 daltons, more preferably from about 2,000 to about 60,000 daltons and, even more preferably, from about 5,000 to about 50,000 daltons. In preferred embodiments, such hydrophilic polymers have average molecular weights of about 5,000 daltons, 10,000 daltons 20,000 daltons and 40,000 daltons.

The peptide compounds of the invention can be derivatized with or coupled to such polymers using any of the methods set forth in Zallipsky (1995)

Bioconjugate Chem

. 6:150-165; Monfardini et al. (1995)

Bioconjugate Chem

. 6:62-69; U.S. Pat. No. 4,640,835; U.S. Pat. No. 4,496,689; U.S. Pat. No. 4,301,144; U.S. Pat. No. 4,670,417; U.S. Pat. No. 4,791,192; U.S. Pat. No. 4,179,337 or WO 95/34326.

In a preferred embodiment, the N-terminus of a peptide of the invention is coupled to a polyethylene glycol molecule. It is particularly preferred that the polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polylactic acid, polyglycolic acid and derivatives and combinations thereof. Most preferably the polymer is polyethylene glycol (PEG), in which case the peptide is referred to as “PEGylated.” PEG is a linear, water-soluble polymer of ethylene oxide repeating units with two terminal hydroxyl groups. PEGs are classified by their molecular weights which typically range from about 500 daltons to about 40,000 daltons. In a presently preferred embodiment, the PEGs employed have an average molecular weight of from about 500 to about 80,000 daltons. It is particularly preferred that the polymer has an average molecular weight of between about 5,000 to 40,000 daltons.

The PEG coupled to the peptide compounds of the invention can be either ranched or unbranched. (See, e.g. Monfardini et al. (1995)

Bioconjugate Chem

. 6:62-69.) PEG is commercially available from Shearwater Polymers, Inc. (Huntsville, Ala.), Sigma Chemical Co. and other companies. Suitable PEGs include, but are not limited to, monomethoxypolyethylene glycol (MePEG-OH), monomethoxypolyethylene glycol-succinate (MePEG-S), monomethoxypolyethylene glycol-succinimidyl succinate (MePEG-S-NHS), monomethoxypolyethylene glycol-amine (MePEG-NH

2

), monomethoxypolyethylene glycol-tresylate (MePEG-TRES) and monomethoxypolyethylene glycol-imidazolyl-carbonyl (MePEG-IM).

Briefly, in one exemplary embodiment, the hydrophilic polymer which is employed, e.g., PEG, is capped at one terminus by an unreactive group such as a methoxy or ethoxy group. Thereafter, the polymer is activated at the other terminus by reaction with a suitable activating agent, such as a cyanuric halide (e.g., cyanuric chloride, bromide or fluoride), diimidazole, an anhydride reagent (e.g., a dihalosuccinic anhydride, such as dibromosuccinic anhydride), acyl azide, p-diazoniumbenzyl ether, 3-(p-diazoniumphenoxy)-2-hydroxypropylether, or the like. The activated polymer is then reacted with a peptide compound of the invention to produce a polymer-derivatized peptide compound. Alternatively, a functional group in the peptide compounds of the invention can be activated for reaction with the polymer, or two groups can be joined in a concerted coupling reaction using known coupling methods. It will be readily appreciated that the peptide compounds of the invention can be derivatized with PEG using a myriad of other reaction schemes known to those of skill in the art.

(ii) Acetylated Compounds

In some instances, the N-terminus of the peptide is acetylated. Preferred acetylated compounds include, by way of example, the following:

Ac-ESGWVW-CONH

2

(SEQ ID NO: 470);

Ac-NSGWVW-CONH

2

(SEQ ID NO: 471); and

Ac-SGWVW-CONH

2

(SEQ ID NO: 472).

The peptides and compounds of the invention can be modified with an acetyl moiety (Ac) using standard techniques known to those skilled in the art. One such technique includes combining the peptide with an acetylating reagent (e.g., acetyl chloride, acetic anhydride) in a suitable solvent to form the acetylated product. To the extent that other acetylated products are formed during the reaction, the N-terminus derivative can be isolated using conventional separation techniques.

D. C-Terminal Modifications:

The peptides and compounds of the invention can advantageously be modified to include an amide functionality at the carboxyl terminus of the peptide. Thus, it is preferred that the C-terminus of the peptide is amidated.

In preparing peptides wherein the C-terminus carboxyl group is replaced by the amide —C(O)NR

3

R

4

where R

3

and R

4

are independently H or lower (C

1-6

) alkyl, a benzhydrylamine resin is preferably used as the solid support for peptide synthesis. Upon completion of the synthesis, a hydrogen fluoride treatment is employed to release the peptide from the support, directly resulting in the free peptide amide (i.e., the C-terminus is —C(O)NH

2

). Alternatively, use of a chloromethylated resin during peptide synthesis coupled with reaction with ammonia (to cleave the side chain protected peptide from the support) yields the free peptide amide and reaction with an alkylamine or a dialkylamine yields a side chain protected alkylamide or dialkylamide (i.e., the C-terminus is —C(O)NR

3

R

4

where R

3

and R

4

are as defined above). Side chain protecting groups are then removed in the usual fashion by treatment with hydrogen fluoride to give the free amides, alkylamides, or dialkylamides.

E. Other Modifications:

One can also replace the naturally occurring side chains of the 20 genetically encoded amino acids (or the stereoisomeric D amino acids) with other side chains, for instance with groups such as alkyl, lower alkyl, cyclic 4-, 5-, 6- or 7-membered alkyl, amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, carboxy and the lower ester derivatives thereof, and 4-, 5-, 6- or 7-membered heterocyclic. In particular, proline analogues in which the ring size of the proline residue is changed from 5 members to 4, 6, or 7 members can be employed.

One can also readily modify the peptides herein by phosphorylation or other methods as described in Hruby et al. (1990)

Biochem J

. 268:249-262. Thus, the peptides of the invention also serve as structural models for non-peptidic compounds with similar biological activity. For example, the peptide backbones may be replaced with a backbone composed of phosphonates, amidates, carbamates, sulfonamides, secondary amines, and N-methylamino acids.

IV. Utility

The compounds of the invention are useful in vitro as unique tools for understanding the biological role of G-CSF, including the evaluation of the many factors thought to influence, and be influenced by, the production of white blood cells. The present compounds are also useful in the development of other compounds that bind to G-CSFR, because the compounds provide important structure-activity relationship (SAR) information that facilitates that development.

Moreover, based on the ability to bind to G-CSFR and related receptors, a compound of the invention can be used as a reagent for detecting a G-CSF receptor or related receptor on living cells, fixed cells, in biological fluids, in tissue homogenates, in purified, natural biological materials, etc. For example, by labeling a compound of the invention, one can identify a cell expressing G-CSFR on its surface. In addition, based on it ability to bind a G-CSFR, a compound of the invention can be used in in situ staining, FACS (fluorescence-activated cell sorting), Western blotting, ELISA (enzyme-linked immunoadsorptive assay), etc. In addition, because of its ability to bind to a G-CSFR, a compound of the invention can be used in receptor purification or in purifying cells expressing G-CSFR on the cell surface (or inside permeabilized cells).

A compound of the invention can also be utilized as a commercial research reagent for various medical research and diagnostic uses. Such uses include but are not limited to: (1) use as a calibration standard for quantitating the activities of candidate G-CSFR antagonists or agonists in a variety of functional assays; (2) use as a blocking reagent in random peptide screening, i.e., in searching for new families of G-CSFR peptide ligands; (3) use in the co-crystallization with G-CSFR, i.e., a compound of the invention will allow formation of crystals bound to G-CSFR, enabling the determination of receptor/peptide structure x-ray crystallography; (4) use in inhibiting or decreasing the proliferation and growth of G-CSF-dependent cell lines; and (5) other research and diagnostic applications wherein the action of G-CSFR is to be mimicked, and the like.

A compound of the invention can also be administered to a warm blooded animal, including a human, to treat a disease that would benefit from the ability of a compound to mimic the effects of G-CSF in vivo. Thus, the present invention encompasses methods for treating a patient who would benefit from a G-CSFR modulator, comprising administering to the patient a therapeutically effective amount of a compound of the invention to activate G-CSFR. For example, a compound of this invention will find use in the treatment of diseases such as a depressed neutrophil count. Although attributable to a myriad of causes, a depressed neutrophil count is commonly associated with chemotherapy, AIDS and pneumonia (particularly community-acquired pneumonia). Thus, it is preferred that a compound of the present invention be used to treat a depressed neutrophil count selected from the group consisting of chemotherapy-induced neutropenia, AIDS-induced neutropenia and community-acquired pneumonia-induced neutropenia.

In addition, the invention encompasses methods for treating a patient who would benefit from a G-CSFR modulator, comprising administering to the patient a therapeutically effective amount of a compound of the invention that antagonizes the action of G-CSF to the G-CSFR in vivo. For example, these receptor antagonists are administered prior to and during chemotherapy to confer chemoprotection to the neutrophil progenitor cells by preventing their proliferation in the presence of cytotoxic drugs. Once chemotherapy administration is suspended, the administration of the chemoprotective G-CSFR antagonists is also suspended thereby allowing the patient's endogenous G-CSF to stimulate proliferation. Alternatively, the neuirophil progenitor cells may be “rescued” by administration of G-CSF or by a G-CSF agonist, e.g., a compound of the present invention having G-CSF agonist activity.

Accordingly, the invention includes pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the invention in association with a pharmaceutical carrier or diluent. The composition can be administered by oral, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous) injection, transdermal (either passively or using iontophoresis or electroporation), or transmucosal (nasal, vaginal, rectal, or sublingual) routes of administration, or using bioerodible inserts, and can be formulated in dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, an additional substance other than an inert diluent, e.g., a lubricating agent such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise a buffering agent. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and syrups, with the elixirs containing an inert diluent commonly used in the art, such as water. These compositions can also include one or more adjuvants, such as a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent or a perfuming agent.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain one or more adjuvants such as a preserving agent, a wetting agent, an emulsifying agent and a dispersing agent. The dosage forms may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, prior to use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, an excipient such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with one or more standard excipients well known in the art.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient is such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, the route of administration, the duration of the treatment desired, and other factors well known to those skilled in the art. Generally, dosage levels of between 0.001 to 10 mg/kg of body weight daily are administered to mammals.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entirety.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to prepare and use the compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. and pressure is at or near atmospheric.

Standard peptide synthetic methods were used, and solid phase reactions were carried out at room temperature. Unless otherwise indicated, all starting materials and reagents were obtained commercially, e.g., from Aldrich, Sigma and ICN, and used without further purification. Standard cell culture and cell harvesting procedures were used.

Also, in these examples and throughout this specification, the abbreviations employed have their generally accepted meanings, as follows:

Ac=acetyl

BSA=bovine serum albumin

DMSO=dimethyl sulfoxide

DTT=dithiothreitol

HPLC=high pressure liquid chromatography

MBP=maltose binding protein

PBS=phosphate-buffered saline

SDS PAGE=sodium dodecyl sulfate polyacrylamide gel electrophoresis

TCEP=tris(2-carboxyethyl) phsophine

TFA=trifluoroacetic acid

Tris=tris[hydroxymethyl]aminomethane

EXAMPLES 1-34

G-CSF Competition Binding Assays

The peptides of Table 1 were synthesized using standard techniques and were subsequently evaluated to identify whether the peptides exhibited specific and/or competitive binding.

Specific binding is binding of a ligand to a specific receptor, as opposed to non-specific binding that is mediated by non-specific interactions. Specific binding may be measured by subtraction of the non-specific binding (measured in the presence of saturating concentrations of unlabeled ligand) from the total binding (measured in the absence of saturating amounts of ligand). Typically, the unlabeled ligand used was a variant of G-CSF in which the cysteine normally found at position 17 was converted to serine (CS17).

Determination of competitive binding was also carried out for a number of peptides. Briefly stated, G-CSFR was purified using standard techniques. The receptor was then immobilized in microtiter plate wells that were coated with acid-treated antibody (A b179) specific for a site on G-CSFR not involved with G-CSF binding. Separately,

125

I was coupled to the natural ligand G-CSF using techniques well known in the art. Test peptides were added to receptor-coated wells and allowed to bind to immobilized receptor for approximately 30 minutes.

125

labeled G-CSF was then introduced to the wells and incubated overnight at 4°C. Unbound

125

I labeled G-CSF was removed by washing the plate several times followed by measuring the amount of radioactivity that remained in each well using conventional techniques. If no reduction in the amount of bound

125

I labeled G-CSF was detected, the peptide did not compete for binding to the receptor. Alternatively, if reduced amounts or no

125

I labeled G-CSF was detected, the peptide did compete. Non-positive results for a particular peptide are not dispositive of that peptide's activity: the peptide may exhibit binding under conditions different from those tested.

The results of these assays reveal important information about the structure activity relationship for peptide and peptide mimetics of the invention to the G-CSF receptor.

TABLE 1

Comp-

Ex.

Specific

etitive

No.

Sequence

Binding?

Binding?

1

CAGEVMHMCC (SEQ ID NO: 8)

Yes

Yes

2

CNREIEAMCC (SEQ ID NO: 9)

Yes

Yes

3

CADEVMHFCC (SEQ ID NO: 10)

Yes

Yes

4

CDVWQLFDRC (SEQ ID NO: 25)

Yes

Yes

5

CSFVQLNSIC (SEQ ID NO: 26)

Yes

Yes

6

CVPWMFYDLC (SEQ ID NO: 29)

Yes

No

7

CDPWMFYDLC (SEQ ID NO: 30)

Yes

No

8

CQRAGYMLAC (SEQ ID NO: 44)

No

No

9

CHANPVWGEC (SEQ ID NO: 45)

No

No

10

CTWTDLESVY (SEQ ID NO: 433)

No

No

11

CFWSDWGQTC (SEQ ID NO: 46)

No

No

12

CPDWYQSYMC (SEQ ID NO: 34)

Yes

Yes

13

CPHWTSYYMC (SEQ ID NO: 47)

Yes

Yes

14

CACMLRVVHC (SEQ ID NO: 43)

Yes

Yes

15

CETLCGACFC (SEQ ID NO: 44)

No

No

16

SNESGWVWLP (SEQ ID NO: 110)

Yes

No

17

EQSNSGWVWV (SEQ ID NO: 111)

Yes

No

18

SRTESGWVWT (SEQ ID NO: 112)

Yes

No

19

QRANSGWVWV (SEQ ID NO: 113)

Yes

No

20

DYDNSGWVWH (SEQ ID NO: 114)

Yes

No

21

ETWGERDWFC (SEQ ID NO: 133)

Yes

Yes

22

STAERLWFCG (SEQ ID NO: 135)

Yes

Yes

23

YETAERSYFC (SEQ ID NO: 119)

Yes

Yes

24

ADNAERGWFC (SEQ ID NO: 137)

Yes

Yes

25

QSNSEREWFC (SEQ ID NO: 138)

Yes

Yes

26

STSERAWFCG (SEQ ID NO: 139)

Yes

Yes

27

ASWSERGWFC (SEQ ID NO: 140)

Yes

Yes

28

ELSSEREWFC (SEQ ID NO: 141)

Yes

Yes

29

DMQGERGWFC (SEQ ID NO: 142)

Yes

Yes

30

DMVYAYPPWS (SEQ ID NO: 155)

Yes

No

31

DEMVYTVPYW (SEQ ID NO: 156)

Yes

Yes

32

HTTNEQFFMC (SEQ ID NO: 434)

Yes

Yes

33

DTWLELESRY (SEQ ID NO: 435)

Yes

No

34

DWQKTIPAYW (SEQ ID NO: 437)

Yes

Yes

EXAMPLES 35-73

G-CSF Radioligand Binding Assays

The peptides of Table 2 were synthesized using standard techniques and were subsequently evaluated to determine their binding affinities to G-CSFR.

Streptavidin-coated scintillation proximity assay (SPA) beads (Amersham) were mixed with biotinylated anti-receptor immobilizing antibody (Ab179) followed by incubation with soluble G-CSFR harvest. Receptor-coated SPA beads were washed twice in PBS/0.1% BSA and distributed to wells of a white polystyrene 96-well microtiter plate (Packard). Serial dilutions of peptide or peptide mimetic were mixed with a constant amount of

125

I labeled G-CSF (10

5

cpm; 1290 Ci/mmol) in PBS/0.1% BSA, added to wells containing receptor-coated SPA beads, and incubated overnight at 4° C. The binding of radiolabeled G-CSF to the receptor-coated SPA bead brings the isotope in close proximity to the scintillant, which allows the emitted radiation to stimulate the scintillant to emit light. Any unbound radiolabeled ligand is not in close enough proximity to the scintillant to allow such energy transfer and hence no signal is generated. The amount of

125

I labeled G-CSF that was bound at equilibrium was measured by counting the plate in a TopCount (Wallac) microtiter plate luminometer. The assay is conducted over a range of peptide concentrations and the results are graphed such that the y-axis represents the amount of bound

125

I labeled G-CSF and the x-axis represents the concentration of peptide or peptide mimetic. One can determine the concentration at which the peptide or peptide mimetic will reduce by 50% (IC

50

) the amount of

125

I labeled G-CSF bound to immobilized G-CSFR. The dissociation constant (K

d

) for the peptide should be similar to the measured IC

50

using the assay conditions described above.

The peptides along with their corresponding IC

50

values are shown in Table 2. lC

50

values are indicated symbolically by the symbols “−”, “+”, and “++”. For examples, those peptides which showed IC

50

values in excess of 200 uM are indicated with a “−”. Those peptides which gave IC

50

values of less than or equal to 200 uM are given a “+”, while those which gave IC

50

values of 500 nM or less are indicated with a “++”. Those peptides, which gave lC

50

values at or near the cutoff point for a particular symbol, are indicated with a hybrid designator, e.g., “+/−”. The peptides for which IC

50

values were not determined are listed as “N.D.”.

The results of these assays reveal important information about the structure-activity relationship for peptide and peptide mimetics of the invention to the G-CSF receptor.

TABLE 2

Ex. No.

Sequence

IC

50

35

NH

2

-EQSNSGWVWV-CONH

2

(SEQ ID NO:111)

+

36

NH

2

-STAERLWFCG-CONH

2

(SEQ ID NO:135)

−

37

+

38

NH

2

-QSNSEREWFC-CONH

2

(SEQ ID NO:138)

−

39

−

40

NH

2

-QSNSEREWFCG-CONH

2

(SEQ ID NO:149)

−

41

−

42

Ac-ESGWVW-CONH

2

(SEQ ID NO:470)

−

43

Ac-NSGWVW-CONH

2

(SEQ ID NO:471)

−

44

Ac-SGWVW-CONH

2

(SEQ ID NO:472)

−

45

NH

2

-EQSNSGWVWVGGGGC-CONH

2

(SEQ ID NO:101)

+

46

+

47

CESRLVECSRM (SEQ ID NO:462)

+/−

48

LAHCLLRLEECAAG (SEQ ID NO:460)

+/−

49

ALLMCESKLAECARAR (SEQ ID NO:450)

+/−

50

+

51

DLWYLESKLEECARRCNG (SEQ ID NO:340)

+

52

+

53

LLDICELKLQECARRCN (SEQ ID NO:208)

++

54

GGGLLDICELKLQECARRCN (SEQ ID NO:209)

++

55

GRTGGGLLDICELKLQECARRCN (SEQ ID NO:210)

++

56

LGIEGRTGGGLLDICELKLQECARRCN (SEQ ID NO:211)

++

57

LLDICELKLQECARRAN (SEQ ID NO:343)

+

58

LLDICELKLQEAARRCN (SEQ ID NO:212)

+

59

Biotin-LLDICELKLQECARRAN (SEQ ID NO:343)

+

60

Biotin-KLLDICELKLQEAARRCN (SEQ ID NO:213)

+

61

LLDIAELKLQECARRCN (SEQ ID NO:463)

+

62

Biotin-KLLDIAELKLQECARRCN (SEQ ID NO:464)

+

63

Biotin-KGGGMLAERKAEERRWFNTHGRE (SEQ ID NO:490)

+

64

+/−

65

N.D.

66

H

2

N-KSTGGLTAERDAEKRRWLLTHGGE-COOH (SEQ ID NO:491)

−

67

+

68

−

69

−

70

YLELCQLRLEECARQFN (SEQ ID NO:282)

+

71

CGCHVSPVQIKALC (SEQ ID NO:198)

+

72

GCHVSPVQIKALC (SEQ ID NO:199)

−

73

HELCETYADWLGCVEW (SEQ ID NO:76)

N.D.

EXAMPLES 74-81

Cell Proliferation and Luminescence Assays

The bioactivity of selected peptides of the invention was measured in cell-based assays. Murine NFS-60 cells proliferate in the presence of G-CSF in a dose dependent manner and were used in standard cell proliferation assays that are well known in the art. Murine IL-3 dependent Ba/F3 cells were co-transfected with expression vectors encoding the full length human G-CSFR and a luciferase reporter gene controlled by the fos promoter. The Ba/F3 G-CSFR reporter cell line is not only dependent on the presence of G-CSF for proliferation, but also produces luciferase in response to the addition of G-CSF in a dose dependent manner. The parental, untransfected cell line does not respond to G-CSF or produce luciferase, but remains IL-3 dependent.

Reporter cell assays were performed on the above cell line using peptides of the invention. The cells were maintained in complete RPMI-164Q media containing 10% fetal calf serum, 2 mM L-glutamine, 1X antibiotic-antimycotic solution (Life Technologies), and 10% WEHI-3 conditioned media (source of murine IL-3). For reporter assays, cells were starved overnight in medium which lacks WEHI-3 to reduce luciferase expression to background levels. The cells were then washed twice in PBS, resuspended in media which lacks WEHI-3 conditioned media, and added to wells of a 96-well microtiter plate containing dilutions of peptide or G-CSF at 5×10

4

cells/well. Plates were incubated for 2 hours at 37° C. in a humidified 5% CO

2

incubator and luciferase activity was measured by the addition of luciferin (LucLite—Packard Biosciences) to each well. The plates were read in a TopCount (Wallac) microtiter plate luminometer.

To measure the ability of selected peptides of the invention to block G-CSF mediated receptor activation, dilutions of peptide were combined with Ba/F3 G-CSFR reporter cells as described above. After a 30-minute incubation at 37° C., G-CSF was added to each well. The cells were incubated for 2 hours at 37° C. and the amount of luciferase produced was measured as described above.

The following seven peptides were tested for bioactivity:

Examples 74, 75, and 76 showed antagonist activity at high concentrations in cell-based assays using NFS-60 cells. The stability of Example 74 in cell culture medium was tested by overnight incubation in NFS-60-conditioned medium; no loss of activity was observed, indicating that the peptide is stable to degradation under these conditions.

Examples 77, 78, 79, and 80 showed cell proliferation activity when fused to the carboxy-terminus of the maltose binding protein (MBP). The MBP fusion protein of Example 78 in particular showed high affinity in a binding competition assay with

125

I-GCSF (IC

50

˜10 nM) and activity in a Ba/F3 G-CSFR cell proliferation assay (maximal activity at 100 nM). Parental Ba/F3 cells and Ba/F3 cells expressing the human thrombopoietin receptor did not proliferate in response to this fusion protein. Western blot analysis of the fusion protein revealed both monomeric and dimeric species, however the G-CSFR preferentially binds the dimeric molecule. This is true for most of the MBP fusions tested. Presumably the fusion protein is dimerized through intermolecular disulfide bonds between cysteine residues present in the peptide sequence. Cleavage of the peptide from the carboxy terminus of MBP using Factor Xa caused the peptide to lose its bioactivity while retaining its binding activity.

The Ba/F3 G-CSFR reporter cell line was used to measure the potency of:

LLDICELKLQECARRCN (SEQ ID NO: 208) Ex. 81

and other possible G-CSF receptor antagonists.

Ligand mediated G-CSF receptor activation in these cells results in the expression of luciferase, providing a detectable biological signal. Ba/F3 G-CSFR reporter cells responded to the addition of G-CSF in a dose dependent manner (FIG.

2

). The addition of increasing concentrations of peptide from Example 81 inhibit this G-CSF response, indicating that the peptide is a G-CSFR antagonist (FIG.

3

).

EXAMPLE 82

Characterization of the Dimer Form of AF15846

The peptide AF15846, i.e., LLDICELKLQECARRCN (SEQ ID NO: 208), was under study as a G-CSF antagonist for chemoprotection against chemotherapy-induced neutropenia. The peptide monomer contains three Cys residues with a mass of 2020.4 (average). This peptide is not active as a monomer but must be oxidized, putatively to a dimer form, for activity.

Monomer vs. Dimer Forms of AF15846:

AF15846 that had been oxidized in 50 mM Tris, pH 8.0 for 48 hours was diluted with PBS, then injected onto a Superdex peptide gel filtration column equilibrated in PBS at 0.75 mL/min. The results of this chromatography indicated that most of the peptide was in dimer form, with small amounts of monomer remaining (not shown). In contrast, AF15846 that had been stored in acid and then diluted with PBS directly prior to injection onto the peptide column eluted predominantly as a monomer. Some dimerization apparently occurred either during storage or during the short period the peptide was at neutral pH prior to and during size exclusion chromatography. Oxidized peptide also eluted much later from a cation exchange column run in salt gradients at low pH, consistent with dimer formation (not shown).

Reverse Phase HPLC Assay for Oxidation of AF15846:

AF15846 was oxidized by incubation in 50 mM Tris, pH 8.0, for 16 to 48 hours. Reverse phase HPLC methods using a Vydac 25 cm C-18 column and 0.1% TFA/acetonitrile buffers were developed to separate the oxidized dimer from unoxidized monomer, and to separate several different dimerized peptide structures. While both high pH reverse phase and cation exchange chromatography were also investigated, low pH reverse phase separation on a 25 cm column provided the best separation of the many oxidized forms of the peptide (not shown). The dimer species elute from the column with earlier retention times than do the monomer species. Samples of oxidized AF15846 were re-reduced with DTT to confirm the elution order. One additional piece of evidence for the formation of intermolecular dimers comes from the fact that when oxidation was carried out at low (0.25 mg/mL) concentrations of peptide, the reaction apparently did not go to completion.

Oxidation of AF15846 Under Various Conditions:

AF15846 was incubated for 48 hours in 50 mM Tris, pH 8, 20% DMSO in water, 20 mM potassium phosphate, pH 3, or 0.1% TFA at room temperature. Aliquots of each sample were taken at various time points. Oxidation of the monomer peptide in Tris resulted in the presence of one major plus one minor oxidized species after several hours. In contrast, oxidation of the peptide in 20% DMSO in water resulted in a complex mixture of oxidized species, even after the 48 hour incubation. Some oxidation of the peptide was observed even at acidic pH, although to a much lesser extent than that observed with either Tris or DMSO as the oxidant.

Activity of Oxidized AF15846 Fractions:

Several fractions containing oxidized AF15846 resulting from treatment under the conditions described above were collected subjected to testing in two assays: an

125

I-G-CSF competition binding assay and an ELISA format competitive G-CSF receptor-binding assay. In both cases fractions corresponding to the predominant Tris-oxidized species exhibited the highest activity. The activity of selected fractions in the

125

I-G-CSF competition binding assay is shown in FIG.

4

. While species corresponding to the monomer peptide were inactive, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) confirmed that the active, Tris-oxidized species was a peptide dimer.

Determination of the Disulfide Structure of the Active Oxidized Form of AF15846:

It was hypothesized that the active form of AF15846 would contain one intrachain disulfide per peptide monomer and one interchain peptide dimer. The three possibilities for this type of structure are shown below

To determine if one of these structures was present in the active form of AF1 5846, aliquots of Tris-oxidized AF15846 (not HPLC purified) were digested with trypsin and subjected to reverse phase HPLC. Trypsin digestion was carried out using an immobilized enzyme column from Perseptive Biosystems. Digestion was carried out in 25 mM Tris, pH 8, 5 mM CaCl

2

. Fractions were eluted from the column directly into 0.1% TFA to lower the pH and minimize disulfide scrambling. The resulting tryptic fragments were separated by reverse phase HPLC and analyzed by MALDI mass spectrometry and Edman sequencing. In addition, an aliquot of the digest was analyzed by electrospray liquid chromatography/mass spectrometry (LC/MS). MALDI MS and sequencing of the tryptic peptides indicated the presence of peptides corresponding to disulfide bonds between Cys-5 and Cys-5, as well as between Cys12 and Cys-12. This finding indicated that there were two interchain disulfide bonds between peptide monomers. This result was confirmed by the LC/MS data (FIG.

5

), which identified peptides identical to those found by MALDI MS. The typtic peptides are labeled, beginning with the first residue, i.e., Lys, as follows: T1=residues 1-8; T2=residues 9-14; T1,2=residues 1-14; T2,3=residues 9-15; and “+” indicates adisulfide linkage between peptides. However, an additional minor species was evidently present, as a peptide corresponding to a disulfide bond between Cys-5 and Cys-12, which could be either an intrachain or an interchain disulfide, was also seen, albeit at a lower level.

To confirm that the active species contained at least two interchain disulfides, an aliquot of the HPLC-purified, Tris-oxidized AF15846 shown to be active in competition assays was also digested with trypsin. The profile of the purified material was compared to that of the unfractionated Tris oxidation product (

FIG. 6

, same labeling as in FIG.

5

). The HPLC profile indicates that the purified material is lacking a peptide corresponding to a Cys-5 to Cys-12 disulfide-linked fragment. This indicated that the active species contains two interchain disulfide bonds. However, the oxidation state of the remaining Cys-16 in each monomer was not determined.

The oxidized peptide was also reacted with N-ethylmaleimide (NEM) at 37° C. for 1 hour in 100 mM ammonium acetate, pH 4.1 to see if any free Cys residues remained in the molecule. If this were the case, treatment with the alkylating reagent would result in a shift of the HPLC retention time. Upon incubation with NEM, no such shift was seen (FIG.

7

). In contrast, when the oxidized peptide was incubated with the disulfide specific reducing agent TCEP, also in ammonium acetate, a shift to a later retention time, consistent with reduced peptide, was found. The reduced peptide was modified with NEM to produce a peptide that eluted even later than the reduced form. These data indicate that all six Cys residues in the AF15846 active dimer are involved in disulfide bonds. Since previous results showed that Cys-5 is linked to Cys-5 and Cys-12 is linked to Cys-12, it seems apparent that the remaining two Cys residues at position 16 of the monomer are also involved in an interchain disulfide bond.

To obtain further information about the disulfide bond structure in active AF15846, the peptide was digested with Lys-C in 50 mM Tris pH 7.0/30% acetontrile. The profile of this digest is shown in FIG.

8

. Four major peaks are seen. The first peak corresponds to a dimer of residues 9-17, as indicated by the MALDI MS spectrum of this fraction. See

FIGS. 9A and 9B

. However, it is not possible to tell with this technique if all four Cys residues are involved in disulfide formation. The last peak contains a dimer of residues 1-8. The remaining two peaks represent intact peptide (22 min) and an artifact peak. This second digest clearly indicates that the peptide dimerizes into a parallel structure.

This three parallel interchain disulfide structure, indicated below, is different than that originally predicted. Note that the arrows represent sites of cleavage by trypsin.

Incubation of the oxidized peptide at 37° C. at higher pH apparently resulted disulfide scrambling and/or degradation of the peptide as control peptide fractions incubated at pH 6.0 or pH 7.5 in parallel with NEM-treated fractions exhibited complex HPLC patterns after incubation. It was necessary to drop to pH 4.1 to obtain clean profiles upon NEM treatment.

A Bioassay for Determining Activity of G-CSF Antagonists:

A biosassay was used to measure the potency of AF15846 and other possible G-CSF receptor antagonists. This bioassay utilizes a Ba/F3 cell line containing the rhGCSF receptor and a c-fos promoter/luciferase gene construct (Ba/F3/rhGCSF-R/pFos-1cf). Competent binding of a ligand to the receptor results in expression of lucifierase as the biological readout. Addition of AF15846 to the assay results in the dose-response curve shifting to higher concentrations, indicating that the peptide is inhibiting the binding of G-CSF to the expressed receptor (FIGS.

10

A and

10

B). Conversely, the inclusion of various levels of peptide in the assay causes an increase in the amount of G-CSF required to produce a signal, also indicating that the peptide inhibits G-CSF binding (FIG.

11

).

491

1

10

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

1
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys
1 5 10

2

9

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

2
Xaa Xaa Xaa Ser Gly Trp Val Trp Xaa
1 5

3

6

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

3
Glu Arg Xaa Xaa Xaa Cys
1 5

4

9

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

4
Xaa Met Val Tyr Xaa Xaa Pro Xaa Trp
1 5

5

12

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

5
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys
1 5 10

6

9

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

6
Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa
1 5

7

10

PRT

Artificial Sequence

Description of Artificial Sequence Formula
peptide sequence

7
Xaa Xaa Xaa Xaa Xaa Glu Xaa Xaa Xaa Xaa
1 5 10

8

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

8
Cys Ala Gly Glu Val Met His Met Cys Cys
1 5 10

9

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

9
Cys Asn Arg Glu Ile Glu Ala Met Cys Cys
1 5 10

10

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

10
Cys Ala Asp Glu Val Met His Phe Cys Cys
1 5 10

11

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

11
Cys Asn Arg Glu Ile Met Trp Met Cys Cys
1 5 10

12

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

12
Cys Ser His Glu Val Trp Trp Tyr Cys Cys
1 5 10

13

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

13
Cys Ser Arg Glu Val Leu Tyr Tyr Cys Cys
1 5 10

14

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

14
Cys Phe Ile Glu Gly Pro Trp Val Cys Cys
1 5 10

15

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

15
Cys Phe Val Glu Gly Asn Trp Tyr Cys Cys
1 5 10

16

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

16
Cys Ala Ala Glu Val Met Val Asn Cys Cys
1 5 10

17

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

17
Cys Ser Asp Glu Val Ile Phe Tyr Cys Cys
1 5 10

18

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

18
Cys Asp Arg Glu Ile Met Trp Phe Cys Cys
1 5 10

19

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

19
Cys Ala His Glu Val Met Trp Met Cys Cys
1 5 10

20

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

20
Cys Gly Ser Glu Val Thr Phe Met Cys Cys
1 5 10

21

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

21
Cys Leu Glu Glu Ile Met Trp Leu Cys Cys
1 5 10

22

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

22
Cys Ala Arg Glu Val Leu Ala Met Cys Cys
1 5 10

23

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

23
Cys Ser Val Glu Val Met Gln Met Cys Cys
1 5 10

24

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

24
Cys Thr Asn Val Gln Leu Met His Tyr Cys
1 5 10

25

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

25
Cys Asp Val Trp Gln Leu Phe Asp Arg Cys
1 5 10

26

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

26
Cys Ser Phe Val Gln Leu Asn Ser Ile Cys
1 5 10

27

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

27
Cys Asp Tyr Trp Gln Trp Phe Asp Lys Cys
1 5 10

28

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

28
Cys Glu Ser Phe Trp Val Glu Leu Trp Cys
1 5 10

29

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

29
Cys Val Pro Trp Met Phe Tyr Asp Leu Cys
1 5 10

30

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

30
Cys Asp Pro Trp Met Phe Tyr Asp Leu Cys
1 5 10

31

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

31
Cys Asp Pro Trp Val Leu Phe Asp Glu Cys
1 5 10

32

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

32
Cys Asp His Trp Thr Tyr Phe Asp Met Cys
1 5 10

33

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

33
Cys Val Val Trp Thr Leu Tyr Asp Lys Cys
1 5 10

34

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

34
Cys Pro Asp Trp Tyr Gln Ser Tyr Met Cys
1 5 10

35

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

35
Cys Pro Asp Trp Tyr Ser Tyr Tyr Met Cys
1 5 10

36

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

36
Cys Pro Glu Trp Tyr Thr Asp Val Met Cys
1 5 10

37

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

37
Cys Pro Asp Trp Tyr Leu Asp Tyr Met Cys
1 5 10

38

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

38
Cys Pro Glu Trp Tyr Leu Asp Tyr Met Cys
1 5 10

39

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

39
Cys Pro Asp Trp Tyr Leu Pro Tyr Met Cys
1 5 10

40

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

40
Cys Pro Glu Trp Tyr Leu Pro Tyr Met Cys
1 5 10

41

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

41
Cys Gln Asp Trp Trp Val Glu Leu Trp Cys
1 5 10

42

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

42
Cys Pro Asp Trp Tyr Leu Pro Trp Met Cys
1 5 10

43

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

43
Cys Ala Cys Met Leu Arg Val Val His Cys
1 5 10

44

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

44
Cys Gln Arg Ala Gly Tyr Met Leu Ala Cys
1 5 10

45

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

45
Cys His Ala Asn Pro Val Trp Gly Glu Cys
1 5 10

46

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

46
Cys Phe Trp Ser Asp Trp Gly Gln Thr Cys
1 5 10

47

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

47
Cys Pro His Trp Thr Ser Tyr Tyr Met Cys
1 5 10

48

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

48
Cys Glu Thr Leu Cys Gly Ala Cys Phe Cys
1 5 10

49

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

49
Cys Ala Thr Thr Ile Asn Asp Thr Leu Cys
1 5 10

50

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

50
Cys Leu Asn Tyr Pro His Pro Val Phe Cys
1 5 10

51

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

51
Cys Met Asp Gly Glu Met Ala Val Asp Cys
1 5 10

52

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

52
Cys Asn Met Gly Trp Met Ser Trp Pro Cys
1 5 10

53

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

53
Cys Glu Thr Tyr Ala Asp Trp Leu Gly Cys
1 5 10

54

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

54
Cys Asp Pro Trp Met Phe Phe Asp Met Cys
1 5 10

55

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

55
Cys Asp Pro Trp Ile Trp Tyr Asp Leu Cys
1 5 10

56

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

56
Cys Asp Pro Trp Ile Met Tyr Asp Arg Cys
1 5 10

57

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

57
Cys Asp Pro Trp Val Phe Phe Asp Ile Cys
1 5 10

58

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

58
Cys Asp Pro Trp Thr Tyr Tyr Asp Leu Cys
1 5 10

59

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

59
Cys Asp Pro Trp Ile Phe Tyr Asp Arg Cys
1 5 10

60

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

60
Cys Asp Pro Trp Leu Phe Tyr Asp Leu Cys
1 5 10

61

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

61
Cys Asp Pro Trp Val Trp Tyr Asp Leu Cys
1 5 10

62

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

62
Cys Asp Pro Trp Ile Phe Phe Asp Arg Cys
1 5 10

63

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

63
Cys Asp Pro Trp Met Phe Phe Asp Gln Cys
1 5 10

64

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

64
Cys Asp Pro Trp Leu Trp Tyr Asp Arg Cys
1 5 10

65

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

65
Cys Asp Val Trp Val Trp Tyr Asp Gln Cys
1 5 10

66

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

66
Cys Asp Pro Trp Ile Tyr Tyr Asp Leu Cys
1 5 10

67

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

67
Cys Val Pro Trp Thr Leu Phe Asp Leu Cys
1 5 10

68

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

68
Cys Pro Ala Trp Tyr Leu Glu Tyr Met Cys
1 5 10

69

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

69
Cys Pro Asp Trp Tyr Leu Glu Tyr Met Cys
1 5 10

70

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

70
Cys Lys Tyr Trp Gln Trp Phe Asp Lys Cys
1 5 10

71

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

71
Cys Asp His Trp Met Trp Tyr Asp Lys Cys
1 5 10

72

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

72
Gly Cys Asn Arg Glu Ile Glu Ala Met Cys Cys Gly
1 5 10

73

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

73
Gly Cys Pro Glu Trp Tyr Thr Asp Val Met Cys Gly
1 5 10

74

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

74
Asn Trp Tyr Cys Met Asp Gly Glu Met Ala Val Asp Cys Glu Ala Thr
1 5 10 15

75

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

75
Trp Gln Ser Cys Asn Met Gly Trp Met Ser Trp Pro Cys Tyr Phe Val
1 5 10 15

76

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

76
His Glu Leu Cys Glu Thr Tyr Ala Asp Trp Leu Gly Cys Val Glu Trp
1 5 10 15

77

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

77
Pro Cys Asp Pro Trp Met Phe Phe Asp Met Cys Glu Arg Trp
1 5 10

78

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

78
Leu Arg Gly Cys Asp Pro Trp Ile Trp Tyr Asp Leu Cys Pro Ala Val
1 5 10 15

79

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

79
Gly Tyr Leu Cys Asp Pro Trp Ile Phe Tyr Asp Arg Cys Leu Gly Phe
1 5 10 15

80

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

80
Arg Phe Ala Cys Asp Pro Trp Val Phe Phe Asp Ile Cys Gly Tyr Trp
1 5 10 15

81

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

81
Gly Tyr Trp Cys Asp Pro Trp Thr Tyr Tyr Asp Leu Cys Leu Thr Ala
1 5 10 15

82

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

82
Met Trp Thr Cys Asp Pro Trp Ile Phe Tyr Asp Arg Cys Phe Leu Asn
1 5 10 15

83

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

83
Gly Ser Ser Cys Asp Pro Trp Leu Phe Tyr Asp Leu Cys Leu Leu Asp
1 5 10 15

84

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

84
Gly Gly Gly Cys Asp Pro Trp Val Trp Tyr Asp Leu Cys Trp Cys Asp
1 5 10 15

85

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

85
Tyr Thr Ser Cys Asp Pro Trp Ile Phe Phe Asp Arg Cys Met Ser Val
1 5 10 15

86

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

86
Asp Pro Tyr Cys Asp Pro Trp Met Phe Phe Asp Gln Cys Ala Tyr Leu
1 5 10 15

87

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

87
Arg Glu Phe Cys Asp Pro Trp Leu Trp Tyr Asp Arg Cys Leu
1 5 10

88

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

88
Asn Thr Gly Cys Asp Val Trp Val Trp Tyr Asp Gln Cys Phe Ala Met
1 5 10 15

89

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

89
Leu Val Phe Cys Asp Pro Trp Ile Tyr Tyr Asp Leu Cys Met Asp Thr
1 5 10 15

90

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

90
Gly Cys Ser Phe Val Gln Leu Asn Ser Ile Cys Gly
1 5 10

91

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

91
Gly Cys Pro Ala Trp Tyr Leu Glu Tyr Met Cys Gly
1 5 10

92

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

92
Gly Cys Pro Asp Trp Tyr Leu Glu Tyr Met Cys Gly
1 5 10

93

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

93
Gly Cys Lys Tyr Trp Gln Trp Phe Asp Lys Cys Gly
1 5 10

94

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

94
Gly Cys Asp His Trp Met Trp Tyr Asp Lys Cys Gly
1 5 10

95

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

95
Ser Asn Glu Ser Gly Trp Val Trp Leu
1 5

96

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

96
Gln Ser Asn Ser Gly Trp Val Trp Val
1 5

97

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

97
Arg Thr Glu Ser Gly Trp Val Trp Thr
1 5

98

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

98
Arg Ala Asn Ser Gly Trp Val Trp Val
1 5

99

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

99
Tyr Asp Asn Ser Gly Trp Val Trp His
1 5

100

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

100
Leu Ser Asp Ser Gly Trp Val Trp Val Pro
1 5 10

101

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

101
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Cys
1 5 10 15

102

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

102
Cys Glu Gln Ser Asn Ser Gly Trp Val Trp Val
1 5 10

103

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

103
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Cys Lys
1 5 10 15
Lys Lys

104

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

104
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys Cys
1 5 10 15

105

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

105
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys
1 5 10

106

13

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

106
Lys Lys Lys Glu Gln Ser Asn Ser Gly Trp Val Trp Val
1 5 10

107

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

107
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys Ser Lys
1 5 10 15
Lys Lys

108

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

108
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Cys Lys Lys Lys
1 5 10 15

109

20

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

109
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Gly Gly
1 5 10 15
Cys Lys Lys Lys
20

110

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

110
Ser Asn Glu Ser Gly Trp Val Trp Leu Pro
1 5 10

111

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

111
Glu Gln Ser Asn Ser Gly Trp Val Trp Val
1 5 10

112

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

112
Ser Arg Thr Glu Ser Gly Trp Val Trp Thr
1 5 10

113

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

113
Gln Arg Ala Asn Ser Gly Trp Val Trp Val
1 5 10

114

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

114
Asp Tyr Asp Asn Ser Gly Trp Val Trp His
1 5 10

115

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

115
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Lys Lys Lys Lys
1 5 10 15

116

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

116
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Ser Lys
1 5 10 15
Lys Lys

117

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

117
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Ser
1 5 10 15

118

30

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

118
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Ser Glu
1 5 10 15
Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Ser
20 25 30

119

20

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

119
Arg Tyr Gln Ser Phe Glu Leu Ser Asp Ser Gly Trp Val Trp Val Pro
1 5 10 15
Val Ala Arg His
20

120

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

120
Glu Arg Asp Trp Phe Cys
1 5

121

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

121
Glu Arg Asp Trp Gly Cys
1 5

122

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

122
Glu Arg Leu Trp Phe Cys
1 5

123

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

123
Glu Arg Ser Tyr Phe Cys
1 5

124

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

124
Glu Arg Gly Trp Phe Cys
1 5

125

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

125
Glu Arg Glu Trp Phe Cys
1 5

126

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

126
Glu Arg Ala Trp Phe Cys
1 5

127

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

127
Glu Arg Leu Tyr Phe Cys
1 5

128

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

128
Glu Arg Tyr Phe Met Cys
1 5

129

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

129
Glu Arg Leu Phe Leu Cys
1 5

130

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

130
Glu Arg Ala Leu Met Cys
1 5

131

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

131
Glu Arg Asp Val Met Cys
1 5

132

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

132
Glu Arg Lys Trp Phe Cys
1 5

133

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

133
Glu Thr Trp Gly Glu Arg Asp Trp Phe Cys
1 5 10

134

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

134
Glu Thr Trp Gly Glu Arg Asp Trp Gly Cys
1 5 10

135

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

135
Ser Thr Ala Glu Arg Leu Trp Phe Cys Gly
1 5 10

136

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

136
Tyr Glu Thr Ala Glu Arg Ser Tyr Phe Cys
1 5 10

137

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

137
Ala Asp Asn Ala Glu Arg Gly Trp Phe Cys
1 5 10

138

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

138
Gln Ser Asn Ser Glu Arg Glu Trp Phe Cys
1 5 10

139

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

139
Ser Thr Ser Glu Arg Ala Trp Phe Cys Gly
1 5 10

140

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

140
Ala Ser Trp Ser Glu Arg Gly Trp Phe Cys
1 5 10

141

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

141
Glu Leu Ser Ser Glu Arg Glu Trp Phe Cys
1 5 10

142

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

142
Asp Met Gln Gly Glu Arg Gly Trp Phe Cys
1 5 10

143

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

143
Ser Ser Ser Glu Arg Ala Trp Phe Cys Gly
1 5 10

144

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

144
Gly Asn Met Arg Glu Arg Leu Tyr Phe Cys
1 5 10

145

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

145
Gln Pro Asn Arg Glu Arg Tyr Phe Met Cys
1 5 10

146

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

146
Ser Val Thr Arg Glu Arg Leu Phe Leu Cys
1 5 10

147

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

147
Ile Pro Leu Ser Glu Arg Ala Leu Met Cys Ser Ser Trp Asn Cys
1 5 10 15

148

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

148
Trp Ala Arg Ser Glu Arg Asp Val Met Cys Leu Ser Tyr Val Cys
1 5 10 15

149

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

149
Gln Ser Asn Ser Glu Arg Glu Trp Phe Cys Gly
1 5 10

150

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

150
Gln Ser Asn Ser Glu Arg Glu Trp Phe Cys Gly Gly Gly Gly Ser
1 5 10 15

151

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

151
Asn Leu Glu Glu Ala Leu Ala Gln Glu Arg Leu Trp Phe Cys Arg Ser
1 5 10 15
Gly Asn Cys

152

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

152
Asn Leu Glu Ser Tyr Glu Met Glu Glu Arg Lys Trp Phe Cys Lys Met
1 5 10 15
Phe Ser Cys

153

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

153
Asp Met Val Tyr Ala Tyr Pro Pro Trp
1 5

154

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

154
Glu Met Val Tyr Thr Val Pro Tyr Trp
1 5

155

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

155
Asp Met Val Tyr Ala Tyr Pro Pro Trp Ser
1 5 10

156

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

156
Asp Glu Met Val Tyr Thr Val Pro Tyr Trp
1 5 10

157

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

157
Cys Glu Ser Arg Leu Val Glu Cys Ser Arg Met Cys
1 5 10

158

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

158
Cys Glu Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys
1 5 10

159

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

159
Cys Gly Glu Arg Leu Ala Glu Cys Ala Arg Leu Cys
1 5 10

160

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

160
Cys Glu Ser Arg Leu Arg Glu Cys Ser Met Leu Cys
1 5 10

161

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

161
Cys Glu Ala Arg Leu Ser Glu Cys Ser Arg Ile Cys
1 5 10

162

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

162
Cys Pro Ala Arg Leu Leu Glu Cys Ser Arg Met Cys
1 5 10

163

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

163
Cys Glu Ser Val Gly Val Gly Asp Trp Trp Ser Cys
1 5 10

164

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

164
Cys Glu Asp Arg Leu Val Glu Gly Pro Trp Val Cys
1 5 10

165

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

165
Cys Asn Asp Gln Phe Arg Thr Cys Val Asp Val Cys
1 5 10

166

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

166
Cys Arg Gly Glu Trp Trp Glu Leu Tyr His Pro Cys
1 5 10

167

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

167
Cys Glu Asp Thr Arg Thr Gly Trp Ala Trp Ser Cys
1 5 10

168

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

168
Cys Thr Trp Leu Ser Ser Gly Glu Leu Val Trp Cys
1 5 10

169

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

169
Cys Trp Pro Pro Val Cys Glu Val Ser Gly Ile Cys
1 5 10

170

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

170
Cys Ser Leu Ser Pro Ile Gln Leu Gln His Leu Cys
1 5 10

171

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

171
Cys Leu Ala Arg Leu Glu Glu Cys Ser Arg Phe Cys
1 5 10

172

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

172
Cys His Asn Ser Ser Pro Met Val Gly Val Thr Cys
1 5 10

173

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

173
Cys His Val Ser Pro Val Gln Ile Lys Ala Leu Cys
1 5 10

174

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

174
Cys Ala Ala Pro Ala Thr Ser Trp Phe Gln Tyr Cys
1 5 10

175

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

175
Cys Ala Ser Lys Leu His Glu Cys Ser Leu Arg Cys
1 5 10

176

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

176
Cys Glu Pro Met Asp Ser Asn Gly Ile Val Gln Cys
1 5 10

177

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

177
Cys Gln Tyr Ala Ser Ala Ala Asp Glu Gln Arg Cys
1 5 10

178

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

178
Cys Glu Tyr Trp Asp Glu Pro Ser Leu Ser Trp Cys
1 5 10

179

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

179
Cys Glu Arg Glu Cys Phe Gln Met Leu Glu Arg Cys
1 5 10

180

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

180
Cys Gly Met Ser Thr Asp Glu Leu Asp Glu Ile Cys
1 5 10

181

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

181
Cys Tyr Val Ser Pro Ser Thr Gly Leu Tyr Ser Cys
1 5 10

182

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

182
Cys Glu Ala Arg Leu Val Glu Cys Ser Arg Leu Cys
1 5 10

183

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

183
Cys Glu Ser Arg Leu Ser Glu Cys Ser Arg Met Cys
1 5 10

184

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

184
Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys
1 5 10

185

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

185
Cys Glu Leu Lys Leu Gln Glu Ala Ala Arg Arg Cys
1 5 10

186

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

186
Cys Leu Glu Arg Leu Glu Glu Cys Ser Arg Phe Cys
1 5 10

187

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

187
Gly Gly Cys Glu Ser Arg Leu Val Glu Cys Ser Arg Met Cys
1 5 10

188

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

188
Gly Gly Cys Glu Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys
1 5 10

189

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

189
Glu Trp Leu Cys Glu Ser Val Gly Val Gly Asp Trp Trp Ser Cys
1 5 10 15

190

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

190
Tyr His Pro Cys Glu Asp Arg Leu Val Glu Gly Pro Trp Val Cys Cys
1 5 10 15
Arg Ser

191

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

191
Trp Leu Leu Cys Asn Asp Gln Phe Arg Thr Cys Val Asp Val Cys Asp
1 5 10 15
Asn Val

192

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

192
Ile Ala Glu Cys Arg Gly Glu Trp Trp Glu Leu Tyr His Pro Cys Leu
1 5 10 15
Ala Ala

193

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

193
Thr Trp Tyr Cys Glu Asp Thr Arg Thr Gly Trp Ala Trp Ser Cys Leu
1 5 10 15
Glu Leu

194

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

194
Gln Leu Asp Cys Thr Trp Leu Ser Ser Gly Glu Leu Val Trp Cys Ser
1 5 10 15
Asp Trp

195

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

195
Gln Phe Asp Cys Thr Trp Leu Ser Ser Gly Glu Leu Val Trp Cys Ser
1 5 10 15
Asp Trp

196

13

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

196
Cys Trp Pro Pro Val Cys Glu Val Ser Gly Ile Cys Ser
1 5 10

197

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

197
Cys Gly Cys Ser Leu Ser Pro Ile Gln Leu Gln His Leu Cys
1 5 10

198

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

198
Cys Gly Cys His Val Ser Pro Val Gln Ile Lys Ala Leu Cys
1 5 10

199

13

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

199
Gly Cys His Val Ser Pro Val Gln Ile Lys Ala Leu Cys
1 5 10

200

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

200
Gly Thr Ser Cys Ala Ala Pro Ala Thr Ser Trp Phe Gln Tyr Cys Val
1 5 10 15
Leu Pro

201

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

201
Arg Met Asp Cys Ala Ser Lys Leu His Glu Cys Ser Leu Arg Cys Ala
1 5 10 15
Tyr Ala

202

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

202
Gly Val Val Cys Glu Pro Met Asp Ser Asn Gly Ile Val Gln Cys Ser
1 5 10 15
Met Arg

203

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

203
Ile Asp Val Cys Gln Tyr Ala Ser Ala Ala Asp Glu Gln Arg Cys Leu
1 5 10 15
Arg Ile

204

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

204
Asn Val Leu Cys Glu Tyr Trp Asp Glu Pro Ser Leu Ser Trp Cys Leu
1 5 10 15
Ser Ser

205

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

205
Cys Gln Cys Glu Arg Glu Cys Phe Gln Met Leu Glu Arg Cys
1 5 10

206

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

206
Phe Cys Ser Cys Gly Met Ser Thr Asp Glu Leu Asp Glu Ile Cys Ala
1 5 10 15
Ile Trp

207

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

207
Glu Glu Val Cys Tyr Val Ser Pro Ser Thr Gly Leu Tyr Ser Cys Tyr
1 5 10 15
Asp Gln

208

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

208
Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

209

20

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

209
Gly Gly Gly Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Cys Ala
1 5 10 15
Arg Arg Cys Asn
20

210

23

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

210
Gly Arg Thr Gly Gly Gly Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln
1 5 10 15
Glu Cys Ala Arg Arg Cys Asn
20

211

27

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

211
Leu Gly Ile Glu Gly Arg Thr Gly Gly Gly Leu Leu Asp Ile Cys Glu
1 5 10 15
Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys Asn
20 25

212

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

212
Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Ala Ala Arg Arg Cys
1 5 10 15
Asn

213

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

213
Lys Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Ala Ala Arg Arg
1 5 10 15
Cys Asn

214

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

214
Glu Glu Lys Leu Arg Glu Cys Ala Arg
1 5

215

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

215
Glu Ala Arg Leu Ala Glu Cys Ala Arg
1 5

216

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

216
Cys Met Lys Leu Met Glu Cys Ala Arg
1 5

217

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

217
Glu Leu Arg Leu Arg Glu Cys Ala His
1 5

218

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

218
Glu Ala Lys Leu His Glu Cys Ala Arg
1 5

219

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

219
Glu Leu Lys Leu Ala Glu Cys Ala Arg
1 5

220

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

220
Glu Ala Arg Leu Glu Glu Cys Ala Arg
1 5

221

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

221
Glu Ala Lys Leu Arg Glu Cys Ala Arg
1 5

222

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

222
Glu Leu Arg Leu Ala Glu Cys Ala Arg
1 5

223

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

223
Glu Ser Arg Leu Ala Glu Cys Ala Arg
1 5

224

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

224
Glu Ala Lys Leu Val Glu Cys Ala Arg
1 5

225

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

225
Glu Ser Arg Leu Arg Glu Cys Ala Arg
1 5

226

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

226
Glu Ala Lys Leu Ala Glu Cys Ala Arg
1 5

227

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

227
Gln Trp Arg Leu Glu Glu Cys Ala Arg
1 5

228

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

228
Gln Leu Arg Leu Glu Glu Cys Ala Arg
1 5

229

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

229
Glu Leu Arg Leu Glu Glu Cys Ala Arg
1 5

230

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

230
Glu Ala Lys Leu Leu Glu Cys Ala Arg
1 5

231

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

231
Glu Ala Arg Ala Gly Val Cys Ala Gly
1 5

232

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

232
Glu Ala Lys Ala Gly Val Cys Ala Gly
1 5

233

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

233
Val Ala Arg Leu Glu Glu Cys Ala Arg
1 5

234

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

234
Glu Leu Lys Leu Asp Glu Cys Ala Arg
1 5

235

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

235
Glu Trp Arg Leu Gln Glu Cys Ala Arg
1 5

236

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

236
Glu Ala Lys Leu Ser Glu Cys Ala Arg
1 5

237

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

237
Glu Ala Arg Leu Ser Glu Cys Ala Arg
1 5

238

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

238
Glu Leu Lys Leu Leu Glu Cys Ala Arg
1 5

239

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

239
Glu Leu Arg Leu Gln Glu Cys Gly Arg
1 5

240

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

240
Glu Gln Lys Leu Ala Glu Cys Ala Arg
1 5

241

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

241
Glu Leu Arg Leu Gln Glu Cys Ala Arg
1 5

242

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

242
Glu Leu Lys Leu Glu Glu Cys Ala Arg
1 5

243

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

243
Glu Ser Arg Leu Glu Glu Cys Ala Arg
1 5

244

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

244
Glu Ala Thr Val Gln Glu Cys Ala Arg
1 5

245

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

245
Glu Leu Lys Leu Gln Glu Cys Ala Arg
1 5

246

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

246
Tyr Ser Arg Leu Glu Glu Cys Gly Arg
1 5

247

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

247
Glu Leu Arg Leu Arg Glu Cys Ala Leu
1 5

248

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

248
Glu Ala Arg Leu Leu Glu Cys Ala Arg
1 5

249

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

249
Glu Ser Arg Leu Leu Glu Cys Ala Arg
1 5

250

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

250
Val Leu Lys Leu Glu Glu Cys Ala Arg
1 5

251

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

251
Glu Ser Lys Leu Ala Glu Cys Ala Arg
1 5

252

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

252
Glu Ser Lys Leu Arg Glu Cys Ala Arg
1 5

253

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

253
Glu Tyr Lys Leu Gly Glu Cys Ala Arg
1 5

254

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

254
Glu Ser Arg Leu Gln Glu Cys Ala Arg
1 5

255

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

255
Gln Ala Arg Leu Ala Glu Cys Ala Arg
1 5

256

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

256
Glu Leu Lys Lys Gln Glu Cys Ala Arg
1 5

257

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

257
Glu Ser Arg Leu Ser Glu Cys Ala Arg
1 5

258

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

258
Glu Ala Arg Leu Glu Glu Cys Gly Arg
1 5

259

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

259
Glu Ser Arg Leu Ala Glu Cys Gly Arg
1 5

260

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

260
Glu Trp Arg Leu Glu Glu Cys Ala Arg
1 5

261

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

261
Glu Ala Arg Leu Ser Glu Cys Gly Arg
1 5

262

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

262
Ala Ala Arg Leu Ala Glu Cys Ala Arg
1 5

263

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

263
Glu Trp Lys Leu Ala Glu Cys Ala Arg
1 5

264

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

264
Glu Ser Lys Leu Glu Glu Cys Ala Arg
1 5

265

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

265
Asp Val Lys Leu Ala Glu Cys Ala Arg
1 5

266

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

266
Glu Leu Gln Leu Glu Glu Cys Ala Arg
1 5

267

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

267
Glu Tyr Lys Leu Ala Ser Cys Ala Arg
1 5

268

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

268
Arg Leu Ser Ile Cys Glu Glu Lys Leu Arg Glu Cys Ala Arg Gly Cys
1 5 10 15

269

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

269
Pro Leu Thr Thr Cys Glu Ala Arg Leu Ala Glu Cys Ala Arg Gln Leu
1 5 10 15

270

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

270
Leu Ala Leu Cys Met Lys Leu Met Glu Cys Ala Arg Arg Tyr
1 5 10

271

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

271
Glu Leu Val Met Cys Glu Leu Arg Leu Arg Glu Cys Ala His Arg Ala
1 5 10 15

272

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

272
Pro Leu Ala Arg Cys Glu Ala Lys Leu His Glu Cys Ala Arg Gln Leu
1 5 10 15

273

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

273
Leu Leu Ser Val Cys Glu Leu Lys Leu Ala Glu Cys Ala Arg Ser Lys
1 5 10 15

274

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

274
Arg Leu Glu Trp Cys Glu Ala Arg Leu Glu Glu Cys Ala Arg Arg Cys
1 5 10 15

275

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

275
Arg Leu Arg Val Val Glu Ala Lys Leu Arg Glu Cys Ala Arg Gly Arg
1 5 10 15

276

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

276
Cys Val Ala His Leu Glu Leu Arg Leu Ala Glu Cys Ala Arg Gln Ile
1 5 10 15

277

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

277
His Leu Ala Arg Cys Glu Ser Arg Leu Ala Glu Cys Ala Arg Gln Leu
1 5 10 15

278

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

278
Arg Leu Ala Leu Leu Glu Ala Lys Leu Val Glu Cys Ala Arg Arg Leu
1 5 10 15

279

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

279
Asp Leu Phe Ser Leu Glu Ser Arg Leu Arg Glu Cys Ala Arg Arg Val
1 5 10 15

280

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

280
Ala Val Pro Val Leu Glu Ala Lys Leu Ala Glu Cys Ala Arg Arg Phe
1 5 10 15

281

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

281
Tyr Leu Gln Gln Leu Gln Trp Arg Leu Glu Glu Cys Ala Arg Gly Met
1 5 10 15

282

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

282
Tyr Leu Glu Leu Cys Gln Leu Arg Leu Glu Glu Cys Ala Arg Gln Phe
1 5 10 15
Asn

283

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

283
Glu Leu His Ile Cys Glu Leu Arg Leu Glu Glu Cys Ala Arg Gly Arg
1 5 10 15

284

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

284
Arg Val Ala Arg Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Lys Ser
1 5 10 15

285

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

285
Tyr Leu Glu Val Leu Glu Ser Arg Leu Ala Glu Cys Ala Arg Trp Lys
1 5 10 15

286

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

286
Glu Ala Lys Leu Leu Glu Cys Ala Arg Ala Arg
1 5 10

287

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

287
Glu Leu Ser Leu Cys Glu Ala Arg Ala Gly Val Cys Ala Gly Ser Val
1 5 10 15
Thr Lys

288

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

288
Glu Leu Ser Leu Cys Glu Ala Lys Ala Gly Val Cys Ala Gly Ser Val
1 5 10 15
Thr Lys

289

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

289
Ala Leu Trp Gln Cys Val Ala Arg Leu Glu Glu Cys Ala Arg Ser Arg
1 5 10 15

290

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

290
Cys Leu Lys Ser Cys Glu Leu Lys Leu Asp Glu Cys Ala Arg Arg Met
1 5 10 15

291

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

291
Ala Leu Gln Thr Cys Glu Trp Arg Leu Gln Glu Cys Ala Arg Ser Arg
1 5 10 15

292

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

292
Tyr Ile Ser Gln Cys Glu Ala Lys Leu Ala Glu Cys Ala Arg Leu Tyr
1 5 10 15

293

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

293
Glu Leu Ser Ser Cys Glu Ala Lys Leu Ser Glu Cys Ala Arg Arg Trp
1 5 10 15

294

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

294
Glu Leu Ser Ser Cys Glu Ala Arg Leu Ser Glu Cys Ala Arg Arg Trp
1 5 10 15

295

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

295
Gln Leu Leu Gln Cys Glu Leu Lys Leu Leu Glu Cys Ala Arg Gln Gly
1 5 10 15

296

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

296
Glu Leu Leu Arg Cys Glu Ala Arg Leu Ala Glu Cys Ala Arg Gly Cys
1 5 10 15

297

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

297
Gln Leu Arg Gln Cys Glu Leu Arg Leu Gln Glu Cys Gly Arg His Gly
1 5 10 15
Asn

298

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

298
Pro Leu Thr Ser Cys Glu Gln Lys Leu Ala Glu Cys Ala Arg Arg Phe
1 5 10 15

299

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

299
Leu Leu Gly Met Cys Glu Leu Arg Leu Gln Glu Cys Ala Arg Ala Lys
1 5 10 15

300

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

300
Glu Leu Ser Arg Cys Glu Leu Lys Leu Glu Glu Cys Ala Arg Gly Met
1 5 10 15

301

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

301
Asp Cys Arg Pro Cys Glu Ser Arg Leu Glu Glu Cys Ala Arg Arg Leu
1 5 10 15

302

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

302
Arg Leu Ser Val Cys Glu Ala Arg Leu Glu Glu Cys Ala Arg Gln Leu
1 5 10 15

303

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

303
Pro Leu Lys Met Cys Glu Ala Thr Val Gln Glu Cys Ala Arg Leu Ile
1 5 10 15

304

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

304
Leu Leu Leu Phe Cys Glu Ala Arg Leu Ser Glu Cys Ala Arg His Val
1 5 10 15

305

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

305
Ser Leu Ser Met Cys Glu Ala Arg Leu Ala Glu Cys Ala Arg Leu Leu
1 5 10 15

306

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

306
Pro Leu Phe Ser Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

307

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

307
Ser Leu Glu Arg Cys Tyr Ser Arg Leu Glu Glu Cys Gly Arg Arg Ile
1 5 10 15

308

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

308
Pro Leu Thr Ser Cys Glu Leu Arg Leu Arg Glu Cys Ala Leu Arg Ser
1 5 10 15
Asn

309

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

309
Lys Leu Ala Ala Cys Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Trp
1 5 10 15

310

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

310
Lys Leu Ala Ala Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Arg Trp
1 5 10 15

311

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

311
Ala Leu Thr Arg Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Lys Ile
1 5 10 15

312

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

312
Leu Leu Gln Gln Cys Glu Leu Lys Leu Ala Glu Cys Ala Arg Ser Ile
1 5 10 15

313

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

313
Gln Leu Trp Gln Cys Glu Ala Arg Leu Leu Glu Cys Ala Arg Arg Ser
1 5 10 15

314

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

314
Arg Leu Arg Leu Cys Glu Ser Arg Leu Leu Glu Cys Ala Arg Ser Leu
1 5 10 15

315

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

315
Gln Leu Glu Thr Cys Val Leu Lys Leu Glu Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

316

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

316
Ala Leu Ser Gln Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Ser Val
1 5 10 15
Thr Lys

317

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

317
Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Ser
1 5 10

318

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

318
Ala Leu Ser Arg Cys Glu Ser Lys Leu Ala Glu Cys Ala Arg Arg Gln
1 5 10 15

319

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

319
Leu Met Ser Thr Cys Glu Ser Lys Leu Arg Glu Cys Ala Arg Ser Leu
1 5 10 15

320

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

320
Ser Leu Gln Arg Cys Glu Tyr Lys Leu Gly Glu Cys Ala Arg Ser Leu
1 5 10 15

321

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

321
Arg Leu Glu Leu Leu Glu Ser Arg Leu Gln Glu Cys Ala Arg Gln Leu
1 5 10 15
Asn

322

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

322
Gln Met Glu Trp Cys Gln Ala Arg Leu Ala Glu Cys Ala Arg Cys Cys
1 5 10 15
Asn

323

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

323
Pro Leu Phe Ser Cys Glu Leu Lys Lys Gln Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

324

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

324
Leu Leu Asp Lys Cys Glu Ser Arg Leu Ser Glu Cys Ala Arg Arg Leu
1 5 10 15

325

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

325
Leu Leu Ala Arg Cys Glu Ala Arg Leu Glu Glu Cys Gly Arg Gln Cys
1 5 10 15

326

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

326
Asp Leu Leu Tyr Cys Glu Ser Arg Leu Ala Glu Cys Gly Arg Met
1 5 10 15

327

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

327
Ala Leu Gln Met Cys Glu Trp Arg Leu Glu Glu Cys Ala Arg Arg Leu
1 5 10 15

328

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

328
Leu Leu Thr Met Cys Glu Ala Arg Leu Ser Glu Cys Gly Arg Arg Leu
1 5 10 15

329

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

329
Ala Leu Trp Arg Cys Glu Ser Arg Leu Ala Glu Cys Ala Arg Arg Ser
1 5 10 15

330

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

330
Leu Leu Ala Thr Cys Ala Ala Arg Leu Ala Glu Cys Ala Arg Gln Leu
1 5 10 15

331

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

331
Leu Gln Thr Cys Glu Trp Lys Leu Ala Glu Cys Ala Arg Ser Asn
1 5 10 15

332

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

332
Pro Leu Arg Ser Cys Glu Ser Lys Leu Glu Glu Cys Ala Arg Gln Leu
1 5 10 15

333

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

333
Cys Leu Arg Ala Leu Asp Val Lys Leu Ala Glu Cys Ala Arg His Leu
1 5 10 15

334

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

334
Arg Leu Lys Thr Leu Glu Leu Gln Leu Glu Glu Cys Ala Arg Arg Ser
1 5 10 15

335

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

335
Lys Leu Arg Asp Val Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Ser
1 5 10 15

336

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

336
Ser Leu Gln Arg Cys Glu Tyr Lys Leu Ala Ser Cys Ala Arg Ser Leu
1 5 10 15

337

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

337
Arg Leu Ala Arg Cys Glu Leu Arg Leu Ala Glu Cys Ala Arg Lys Ser
1 5 10 15

338

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

338
Asp Leu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

339

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

339
Asp Leu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Cys Ala Arg Arg Ala
1 5 10 15
Asn Gly

340

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

340
Asp Leu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn Gly

341

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

341
Lys Gln Arg Glu Leu Glu Leu Lys Leu Ala Glu Cys Ala Arg Arg Ser
1 5 10 15

342

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

342
Gln Met Gln Glu Trp Cys Ala Arg Leu Ala Glu Cys Ala Arg Cys Cys
1 5 10 15
Asn

343

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

343
Leu Leu Asp Ile Cys Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Ala
1 5 10 15
Asn

344

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

344
Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp
1 5 10

345

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

345
Ala Glu Arg Tyr Ala Glu Glu Arg Glu Gly
1 5 10

346

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

346
Ala Glu Arg Met Ala Glu Glu Arg Arg Trp
1 5 10

347

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

347
Ala Glu Arg Lys Ala Glu Glu Arg Arg Arg
1 5 10

348

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

348
Ala His Arg Asn Ala Glu Glu Arg Arg Trp
1 5 10

349

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

349
Ala Glu Arg Lys Ser Glu Asp Trp Arg Trp
1 5 10

350

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

350
Ala Glu Arg Lys Ala Glu Glu Lys Arg Arg
1 5 10

351

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

351
Ala Glu Arg Gln Ala Glu Thr Arg Arg Trp
1 5 10

352

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

352
Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp
1 5 10

353

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

353
Ala Glu Arg Gln Ala Glu Glu Arg Arg Trp
1 5 10

354

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

354
Ala Glu Arg Arg Ala Glu Glu Arg Arg Trp
1 5 10

355

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

355
Ala Glu Arg Asp Ala Glu Gln Arg Arg Trp
1 5 10

356

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

356
Ala Glu Arg Ile Ala Glu Glu Arg Arg Trp
1 5 10

357

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

357
Ala Glu Arg Ser Ala Glu Glu Arg Arg Trp
1 5 10

358

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

358
Ala Glu Arg Lys Ala Glu Glu Leu Arg Trp
1 5 10

359

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

359
Ala Glu Arg Lys Ala Glu Glu Ser Arg Trp
1 5 10

360

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

360
Glu Glu Arg Lys Ala Glu Glu Arg Arg Trp
1 5 10

361

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

361
Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp
1 5 10

362

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

362
Ala Asp Gly Lys Ala Glu Glu Leu Arg Trp
1 5 10

363

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

363
Ala Asp Gly Met Pro Glu Glu Arg Arg Trp
1 5 10

364

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

364
Ala Asp Gly Glu Ala Glu Lys Arg Arg Trp
1 5 10

365

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

365
Ala Asp Gly Asn Ala Glu Glu Arg Arg Trp
1 5 10

366

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

366
Ala Asp Gly Glu Ala Glu Lys Ala Arg Trp
1 5 10

367

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

367
Ala Glu Gly Glu Ala Glu Lys Ala Arg Trp
1 5 10

368

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

368
Gly Glu Arg Lys Ala Glu Glu Arg Arg Trp
1 5 10

369

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

369
Ala Glu Arg Glu Ala Glu Glu Arg Arg Trp
1 5 10

370

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

370
Ala Asp Gly Glu Ala Glu Ala Arg Arg Trp
1 5 10

371

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

371
Ala Asp Gly Arg Ala Glu Glu Ala Arg Trp
1 5 10

372

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

372
Ala Glu Gly Arg Ala Glu Glu Ala Arg Trp
1 5 10

373

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

373
Ala Glu Arg Glu Ala Glu Lys Ala Arg Trp
1 5 10

374

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

374
Ala Glu Arg Lys Ala Glu Glu Gln Arg Trp
1 5 10

375

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

375
Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp
1 5 10

376

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

376
Ala Glu Arg Glu Ala Glu Lys Leu Arg Trp
1 5 10

377

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

377
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr His
1 5 10 15
Gly Arg Glu

378

20

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

378
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr His
1 5 10 15
Gly Arg Glu Lys
20

379

22

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

379
Gly Gly Gly Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe
1 5 10 15
Asn Thr His Gly Arg Glu
20

380

20

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

380
Cys Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr
1 5 10 15
His Gly Arg Glu
20

381

21

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

381
Cys Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Thr
1 5 10 15
His Gly Arg Glu Lys
20

382

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

382
Met Leu Ala Glu Arg Tyr Ala Glu Glu Arg Glu Gly Phe Asn Met Gln
1 5 10 15
Trp Arg Glu

383

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

383
Met Leu Ala Glu Arg Met Ala Glu Glu Arg Arg Trp Phe Arg Arg Met
1 5 10 15
Gly

384

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

384
Ile Val Ala Glu Arg Lys Ala Glu Glu Arg Arg Arg Leu Asn Thr Glu
1 5 10 15
Gly His Glu

385

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

385
Ile Leu Ala His Arg Asn Ala Glu Glu Arg Arg Trp Phe Gln Lys His
1 5 10 15
Gly Arg

386

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

386
Met Leu Ala Glu Arg Lys Ser Glu Asp Trp Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Asp

387

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

387
Met Leu Ala Glu Arg Lys Ala Glu Glu Lys Arg Arg Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

388

21

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

388
Ile Leu Ala Glu Arg Gln Ala Glu Thr Arg Arg Trp Met Arg Asn Ala
1 5 10 15
Gly Ser Val Thr Lys
20

389

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

389
Met Leu Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp Leu Lys Arg Gln
1 5 10 15
Cys Gly

390

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

390
Met Leu Ala Glu Arg Gln Ala Glu Glu Arg Arg Trp Leu Lys Met His
1 5 10 15
Gly Gly Glu

391

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

391
Met Leu Ala Glu Arg Arg Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Gly Asp

392

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

392
Met Leu Ala Glu Arg Gln Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Asp

393

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

393
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Lys Thr His
1 5 10 15
Gly Arg Glu

394

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

394
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Asn Asn Gln
1 5 10 15
Gly Arg Glu

395

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

395
Met Pro Ala Glu Arg Asp Ala Glu Gln Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Glu

396

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

396
Ile Leu Ala Glu Arg Ile Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg

397

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

397
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Gln Thr His
1 5 10 15
Gly Arg Glu

398

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

398
Ile Leu Ala Glu Arg Ser Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

399

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

399
Leu Leu Ala Glu Arg Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Glu

400

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

400
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Gln Thr His
1 5 10 15
Gly Arg Glu

401

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

401
Met Leu Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp
1 5 10

402

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

402
Met Phe Ala Glu Arg Lys Ala Glu Glu Ser Arg Trp Leu Gln Ser Gln
1 5 10 15
Gly Arg Glu

403

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

403
Met Leu Glu Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg

404

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

404
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Met Gln
1 5 10 15
Gly Arg Glu

405

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

405
Met Leu Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp Phe Tyr Thr His
1 5 10 15
Gly Arg Glu

406

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

406
Met Leu Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Leu Asp

407

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

407
Met Ile Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Asp

408

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

408
Met Leu Ala Asp Gly Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Ser Asp

409

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

409
Met Leu Ala Glu Arg Asn Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Asp

410

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

410
Met Leu Ala Asp Gly Lys Ala Glu Glu Leu Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

411

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

411
Ile Leu Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Arg Asp

412

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

412
Met Leu Ala Asp Gly Met Pro Glu Glu Arg Arg Trp Leu Gln Thr His
1 5 10 15
Gly Arg Asp

413

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

413
Met Leu Ala Asp Gly Glu Ala Glu Lys Arg Arg Trp Leu Asn Thr His
1 5 10 15
Gly Arg Asp

414

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

414
Met Leu Ala Asp Gly Asn Ala Glu Glu Arg Arg Trp Leu Met Thr His
1 5 10 15
Gly Arg Asp

415

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

415
Met Leu Ala Asp Gly Glu Ala Glu Lys Ala Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

416

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

416
Met Leu Ala Glu Gly Glu Ala Glu Lys Ala Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

417

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

417
Met Leu Ala Asp Gly Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

418

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

418
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Ser Ala His
1 5 10 15
Val Arg Glu

419

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

419
Leu Leu Gly Glu Arg Lys Ala Glu Glu Arg Arg Trp Tyr Lys Thr His
1 5 10 15
Ala Arg Glu

420

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

420
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Met Thr His
1 5 10 15
Gly His Asp

421

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

421
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Ser Gln
1 5 10 15
Cys Leu Glu

422

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

422
Leu Leu Ala Glu Arg Glu Ala Glu Glu Arg Arg Trp Phe Lys Thr His
1 5 10 15
Gly Arg Glu

423

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

423
Met Leu Ala Asp Gly Glu Ala Glu Ala Arg Arg Trp Phe Asn Met His
1 5 10 15
Gly Arg Glu

424

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

424
Met Leu Ala Asp Gly Arg Ala Glu Glu Ala Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Ser Glu

425

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

425
Met Leu Ala Glu Gly Arg Ala Glu Glu Ala Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Ser Glu

426

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

426
Met Leu Ala Glu Arg Glu Ala Glu Lys Ala Arg Trp Leu Lys Thr Gln
1 5 10 15
Gly Arg Glu

427

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

427
Met Met Ala Glu Arg Lys Ala Glu Glu Gln Arg Trp Phe Asp Ile His
1 5 10 15
Gly Arg Asp

428

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

428
Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His
1 5 10 15
Gly Gly Glu

429

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

429
Met Leu Ala Glu Arg Gln Ala Glu Glu Arg Arg Trp Leu Lys Ser Gln
1 5 10 15
Arg Gly Glu

430

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

430
Leu Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Phe Ala Thr His
1 5 10 15
Gly Arg Asp

431

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

431
Met Leu Ala Glu Arg Glu Ala Glu Lys Leu Arg Trp Leu Lys Ser Gln
1 5 10 15
Glu Arg Ala

432

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

432
Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp Leu Lys Thr His
1 5 10 15
Gly Gly Glu

433

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

433
Cys Thr Trp Thr Asp Leu Glu Ser Val Tyr
1 5 10

434

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

434
His Thr Thr Asn Glu Gln Phe Phe Met Cys
1 5 10

435

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

435
Asp Thr Trp Leu Glu Leu Glu Ser Arg Tyr
1 5 10

436

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

436
His Asn Ser Ser Pro Met Val Gly Val Thr
1 5 10

437

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

437
Asp Trp Gln Lys Thr Ile Pro Ala Tyr Trp
1 5 10

438

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

438
Arg Trp Gly Arg Glu Gly Leu Val Ala Ala Leu Leu
1 5 10

439

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

439
Trp Ser Gly Thr Arg Val Trp Arg Cys Val Val Thr
1 5 10

440

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

440
Met Ser Leu Leu Ser Tyr Leu Arg Ser
1 5

441

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

441
Leu Asp Leu Leu Ala Ile
1 5

442

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

442
Arg Ile Tyr Gly Val Lys
1 5

443

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

443
Met Ile Trp His Met Phe Met Ser Leu Leu Phe
1 5 10

444

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

444
Phe Phe Trp Ala Ser Trp Met His Leu Leu Trp
1 5 10

445

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

445
Phe Asp Asp Cys Trp Arg Glu Arg Glu Gln Phe Leu Phe Gln Ala Leu
1 5 10 15

446

13

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

446
Cys Gly Arg Ala Ser Glu Cys Phe Arg Leu Leu Glu Met
1 5 10

447

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

447
Arg Glu Cys Phe Gln Met Leu Glu Arg
1 5

448

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

448
Cys Ser Ile Arg Trp Asp Phe Val Pro Gly Tyr Gly Leu Cys
1 5 10

449

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

449
Trp Met Gln Cys Trp Asp Ser Leu Ser Leu Cys Tyr Asp Met
1 5 10

450

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

450
Ala Leu Leu Met Cys Glu Ser Lys Leu Ala Glu Cys Ala Arg Ala Arg
1 5 10 15

451

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

451
Leu Ala His Cys Lys Lys Arg Lys Glu Glu Cys Ala Ala Gly
1 5 10

452

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

452
Ser Ile Asp Gly Val Tyr Leu Arg Thr Ser Arg Thr
1 5 10

453

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

453
Ser Ile Asp Gly Val Tyr Leu Arg Thr Arg Ser Arg Thr Arg Tyr
1 5 10 15

454

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

454
Val Arg Trp Leu Arg Gly Ser Thr Leu Arg Gly Leu Arg Asp Arg
1 5 10 15

455

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

455
Asp Arg Gly Gly Gly Thr Val Gly Val Tyr Trp Trp Glu Ser Tyr
1 5 10 15

456

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

456
Val Trp Gly Thr Val Gly Thr Trp Leu Glu Tyr
1 5 10

457

7

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

457
Leu Met Trp Val Ser Ala Tyr
1 5

458

16

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

458
Arg Ala Ser Asp Glu Tyr Gly Ala Leu Val Arg Phe Cys Thr Asn Leu
1 5 10 15

459

13

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

459
Asn Tyr Trp Cys Asp Ser Asn Trp Val Cys Glu Ile Ala
1 5 10

460

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

460
Leu Ala His Cys Leu Leu Arg Leu Glu Glu Cys Ala Ala Gly
1 5 10

461

14

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

461
Leu Ala Leu Cys Leu Ala Arg Leu Arg Glu Cys Ala Gly Gly
1 5 10

462

11

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

462
Cys Glu Ser Arg Leu Val Glu Cys Ser Arg Met
1 5 10

463

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

463
Leu Leu Asp Ile Ala Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg Cys
1 5 10 15
Asn

464

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

464
Lys Leu Leu Asp Ile Ala Glu Leu Lys Leu Gln Glu Cys Ala Arg Arg
1 5 10 15
Cys Asn

465

25

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

465
Cys Ser Thr Gly Gly Gly Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg
1 5 10 15
Arg Trp Leu Leu Thr His Gly Gly Glu
20 25

466

21

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

466
Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His
1 5 10 15
Gly Gly Glu Gly Gly
20

467

22

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

467
Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His
1 5 10 15
Gly Gly Glu Gly Gly Lys
20

468

24

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

468
Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His
1 5 10 15
Gly Gly Glu Gly Gly Gly Gly Gly
20

469

25

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

469
Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg Trp Leu Leu Thr His
1 5 10 15
Gly Gly Glu Gly Gly Gly Gly Gly Lys
20 25

470

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

470
Glu Ser Gly Trp Val Trp
1 5

471

6

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

471
Asn Ser Gly Trp Val Trp
1 5

472

5

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

472
Ser Gly Trp Val Trp
1 5

473

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

473
Pro Leu Gly Lys Cys Glu Ala Thr Cys Arg Glu Met Ala Arg Tyr Phe
1 5 10 15
Asn

474

17

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

474
Ser Leu Gln Arg Cys Glu Tyr Lys Leu Ala Ser Val Arg Gly Leu Cys
1 5 10 15
Asn

475

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

475
Asp Leu Trp Tyr Leu Glu Ser Lys Leu Glu Glu Ala Ala Arg Arg Cys
1 5 10 15
Asn Gly

476

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

476
Pro Tyr Met Gly Thr Arg Ser Arg Ala Lys Leu Leu Arg Gln Gln
1 5 10 15

477

15

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

477
Arg Asn Ala Gly Glu Arg Arg Trp Phe Lys Thr Gln Gly Trp Tyr
1 5 10 15

478

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

478
Met Leu Ala Glu Arg Asn Ala Asp Asp Arg Arg Trp Phe Asn Thr His
1 5 10 15
Gly Arg Asp

479

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

479
Met Met Ala Asp Gly Arg Leu Arg Asn Ser Val Gly Leu Ile Leu Trp
1 5 10 15
Cys Asp

480

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

480
Met Leu Ala Asp Gly Arg Leu Arg Asn Val Val Gly
1 5 10

481

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

481
Leu Leu Ala Asp Val Arg Arg Arg Asn Gly Val Gly Leu Leu Arg Met
1 5 10 15
Gly Arg Asp

482

12

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

482
Met Leu Ala Asp Gly Arg Leu Arg Asn Phe Gly Gly
1 5 10

483

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

483
Thr Tyr Met Thr Tyr Val Tyr Trp Leu Cys
1 5 10

484

8

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

484
Arg Phe Gly Glu Arg Trp Gly Leu
1 5

485

9

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

485
His Trp Leu Trp Trp Gly Trp Asn Phe
1 5

486

10

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

486
Arg Glu Cys Phe Gln Met Leu Glu Arg Cys
1 5 10

487

18

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

487
Ile Leu Ala His Arg Asn Ala Lys Glu Arg Arg Trp Phe Gln Lys His
1 5 10 15
Gly Arg

488

26

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

488
Cys Ser Thr Gly Gly Gly Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg
1 5 10 15
Arg Trp Leu Leu Thr His Gly Gly Glu Lys
20 25

489

23

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

489
Lys Gly Gly Gly Met Leu Ala Glu Arg Lys Ala Glu Glu Arg Arg Trp
1 5 10 15
Phe Asn Thr His Gly Arg Glu
20

490

24

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

490
Lys Ser Thr Gly Gly Leu Thr Ala Glu Arg Asp Ala Glu Lys Arg Arg
1 5 10 15
Trp Leu Leu Thr His Gly Gly Glu
20

491

19

PRT

Artificial Sequence

Description of Artificial Sequence Synthetic
peptide

491
Glu Gln Ser Asn Ser Gly Trp Val Trp Val Gly Gly Gly Gly Cys Lys
1 5 10 15
Lys Lys Cys

Number	Name	Date	Kind
5298603	Habermann et al.	Mar 1994	A
5358707	Reichert et al.	Oct 1994	A
5589456	Smith et al.	Dec 1996	A
5651963	Halenbeck et al.	Jul 1997	A
5773581	Camble et al.	Jun 1998	A
5824778	Ishikawa et al.	Oct 1998	A
6100070	Zurfluh et al.	Aug 2000	A

Compounds having affinity for the granulocyte-colony stimulating factor receptor (G-CSFR) and associated uses

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Term Extension

Abstract

Description

Claims

US Referenced Citations (7)

Foreign Referenced Citations (1)