Conjugates activated by cell surface proteases and therapeutic uses thereof

• US 20040001801A1
• Filed: 05/23/2002
• Published: 01/01/2004
• Est. Priority Date: 05/23/2002
• Status: Abandoned Application

• Current Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Original Assignee: Corvas International, Inc. (Bausch Health Cos., Inc.)
• Inventors: Siev, Daniel Vanna, Madison, Edwin L., Kemp, Scott Jeffrey, Komandla, Mallareddy, Vlasuk, George P., Semple, Joseph Edward
• Application Number:
  US10/156,214
• Publication Number:
  US 20040001801A1
• Time in Patent Office: Days
• US Class Current: 424/85.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/2006 IL-1
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 9/6424 Serine endopeptidases (3.4.21)

Abstract

Conjugates, compositions and methods for treatment, prevention, or amelioration of one or more symptoms of cell surface protease-related diseases, including MTSP-related, urokinase-type plasminogen activator (uPA) or endotheliase-related diseases, are provided. The conjugates for use in the compositions and methods are peptidic conjugates that contain therapeutic, including cytotoxic, agents.

Claims

1. A conjugate, comprising a therapeutic agent and a peptidic substrate linked thereto optionally via a linker, wherein the peptidic substrate is proteolytically cleaved by a cell surface protease or a soluble, released or shed form thereof, to liberate the therapeutic agent, wherein the conjugate is not substantially cleaved by plasmin or prostate specific antigen (PSA).

2. The conjugate of claim 1, wherein the liberated therapeutic agent is active.

3. The conjugate of claim 1, wherein cleavage liberates the therapeutic agent in a form that requires further processing for activation.

4. The conjugate of claim 1 that comprises the components:

(peptidic substrate)_s, (Linker)_q, and (therapeutic agent)_t;

wherein at least one peptidic substrate moiety is linked with or without a linker to at least one therapeutic agent, s is 1 to 6, q is 0 to t, and t is 1 to 6, wherein a cell surface protease that cleaves the peptidic substrate(s) results in delivery of the therapeutic agent to the cell.

5. The conjugate of claim 1, wherein the peptidic substrate comprises one amino acid or more, wherein, upon proteolytic cleavage of the conjugate, the resulting therapeutic agent is active or in a form that, upon further processing, is active.

6. The conjugate of claim 1, wherein the cell surface protease is a serine protease.

7. The conjugate of claim 1, wherein the cell surface protease is a type II transmembrane serine protease (MTSP) or an endotheliase.

8. The conjugate of claim 1, wherein the cell surface protease is selected from endotheliase 1, endotheliase 2, MTSP1, MTSP3, MTSP4, MTSP6, MTSP7, MTSP9, MTSP10, MTSP12, MTSP20, MTSP22, MTSP25, corin, enterokinase, human airway trypsin-like protease (HAT), TMPRSS2, hepsin, urokinase-type plasminogen activator (uPA), and TMPRSS4.

9. The conjugate of claim 1, wherein the cell surface protease comprises a polypeptide selected from the group consisting of

a polypeptide comprising the sequence of amino acids set forth in any of SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 270, 272, 274 and 276;

a polypeptide encoded by a sequence of nucleotides that hybridizes under conditions of high stringency to the sequence of nucleotides set forth in any of SEQ ID Nos 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 38, 40, 42, 44, 269, 273 and 275;

a polypeptide that comprises a sequence of amino acids having at least about 40% sequence identity with the sequence of amino acids set forth in SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 270, 272, 274 and 276; and

a polypeptide encoded by a splice variant of the sequence of nucleotides set forth in any of SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 270, 272, 274 and 276.

10. The conjugate of claim 1, wherein the therapeutic agent is a toxin, a small organic molecule, a nucleic acid, protein therapeutic agents, a cytokine or a growth factor.

11. The conjugate of claim 1, wherein the therapeutic agent is an anti-cancer agent.

12. The conjugate of claim 1, wherein the therapeutic agent is an anti-angiogenic agent.

13. The conjugate of claim 1, wherein the therapeutic agent is selected from abrin, ricin A, pseudomonas exotoxin shiga toxin, diphtheria toxin, a tumor necrosis factor, α

-interferon, γ

-interferon, nerve growth factor, tissue factor and tissue factor variants, FAS-ligand platelet derived growth factor, tissue plasminogen activator, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GMCSF), granulocyte colony stimulating factor (G-CSF), erythropoietin (EPO), nerve growth factor, fibroblast growth factors (FGFs), and epidermal growth factor.

14. The conjugate of claim 1, wherein the therapeutic agent is selected from alkylating agents, toxins, antiproliferative agents, pro-apoptotic agents, pro-coagulants, cytotoxic nucleosides and tubulin binding agents.

15. The conjugate of claim 1, wherein the therapeutic agent is selected from among the following classes of drugs:

a) anthracycline family of drugs,

b) vinca alkaloid drugs,

c) mitomycins,

d) bleomycins,

e) cytotoxic nucleosides,

f) pteridine family of drugs.

g) diynenes,

h) estramustine,

i) cyclophosphamide,

j) taxanes,

k) podophyllotoxins,

l) maytansanoids,

m) epothilones, and

n) combretastatin and analogs,

or pharmaceutically acceptable derivatives thereof.

16. The conjugate of claim 1, wherein the therapeutic agent is selected from among the following drugs:

a) doxorubicin,

b) carminomycin,

c) daunorubicin,

d) aminopterin,

e) methotrexate,

f) methopterin,

g) dichloromethotrexate,

h) mitomycin C,

i) porfiromycin,

j) 5-fluorouracil,

k) 6-mercaptopurine,

l) cytosine arabinoside,

m) podophyllotoxin,

n) etoposide,

o) etoposide phosphate,

p) melphalan,

q) vinblastine,

r) vincristine,

s) leurosidine,

t) vindesine,

u) estramustine,

v) cisplatin,

w) cyclophosphamide,

x) taxol,

y) leurositte,

z) 4-desacetylvinblastine,

aa) epothilone B,

bb) taxotere,

cc) maytansanol,

dd) epothilone A, and

ee) combretastatin and analogs;

or a pharmaceutically acceptable derivative thereof.

17. The conjugate of claim 1, further comprising a linker between the therapeutic agent and the peptidic substrate.

18. The conjugate of claim 17, wherein the linker comprises a carbohydrate, peptide, and/or hydrocarbon core.

19. The conjugate of claim 17, wherein the linker comprises:

a biscarbonyl alkyl diradical whereby an amine moiety on the therapeutic agent is connected with the linker unit to form an amide bond and the amino terminus of the peptidic substrate is connected with the other end of the linker unit also forming an amide bond;

or

a diaminoalkyl diradical linker unit, whereby a carbonyl moiety on the therapeutic agent is covalently attached to one of the amines of the linker unit while the other amine of the linker unit is covalently attached to the C-terminus of the peptidic substrate;

or

is a self-eliminating linker of the following formulae;

where A is NH or O;

D is N(H or alkyl) or O;

R²⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substituted with 1 or more, such as, for example, 1 to 3, substituents selected from halo, halo alkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)yl groups, halo, pseudohalo, cyano, hydroxy, haloalkyl and polyhaloalkyl, such as, for example, halo lower alkyl, especially trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl that optionally is substituted with 1 or more, such as, for example, 1 to 3, substituents, for example, selected from halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylamino-carbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl; and

y is an integer from 1 to 3.

20. The conjugate of claim 17, wherein the linker is a diamine comprising a cyclic alkylene moiety.

21. The conjugate of claim 17, wherein the diamine contains a bicycloalkylene moiety.

22. The conjugate of claim 17, wherein the linker selected from 1,4-bis(aminomethyl)cyclohexane, 1,4-bis(aminomethyl)cycloheptane, 1,3-bis(aminomethyl)cyclopentane, 1-amino-4-(aminomethyl)cyclohexane, 1,4-diaminocyclohexane and 1,4-bis(aminomethyl)bicyclo[2.2.2]octane.

23. The conjugate of claim 17, wherein the linker is a 1,ω

-diaminoalkane.

24. The conjugate of claim 17, wherein the linker is a 1,3-diaminopropane.

25. The conjugate of claim 17, wherein the linker is a 1,ω

-dicarbonylalkane.

26. The conjugate of claim 25, wherein the linker selected from oxalic, malonic, succinic, glutaric, adipic and pivalic acids.

27. The conjugate of claim 1, wherein the peptidic substrate comprises P1 that is any amino acid.

28. The conjugate of claim 27, wherein P1 is a naturally-occurring amino acid.

29. The conjugate of claim 27, wherein P1 is an amino acid with an aromatic, branched, or branched aromatic side chain.

30. The conjugate of claim 1, wherein the peptidic substrate comprises P1, where P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr.

31. The conjugate of claim 1, wherein:

the peptidic substrate comprises a P1-P1′

bond;

the P1-P1′

bond is the site of cleavage by a cell surface protease;

P1 is selected from Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; and

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl.

32. The conjugate of claim 1, wherein the peptidic substrate comprises P1, wherein P1 is Arg, Lys or an Arg surrogate.

33. The conjugate of claim 1, further comprising a P2 residue selected from Phe, Ser, Gly and Ala.

34. The conjugate of claim 1, further comprising a P3 residue selected from Arg, Lys, Gln, Ser, Quat and Arg surrogates.

35. The conjugate of claim 1, further comprising a P4 residue selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val.

36. The conjugate of claim 1, further comprising a P5 residue selected from Arg and Arg surrogates.

37. The conjugate of claim 1, further comprising a P6 residue selected from Leu, Ile and Val.

38. The conjugate of claim 1, further comprising a P2′

residue selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

39. The conjugate of claim 1, further comprising a P3′

residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

40. The conjugate of claim 1, wherein:

the peptidic substrate comprises a 5-mer that has the formula;

P4-P3-P2-P1-P1′

, wherein;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gln, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val; and

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl.

41. The conjugate of claim 40, wherein:

the peptidic substrate optionally further comprises one or more of a P5 or P2′

amino acid residue, wherein;

P5 is Arg or an Arg surrogate; and

P2′

is selected from among Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

42. The conjugate of claim 41, wherein:

if the peptidic substrate comprises a P5 amino acid residue, then the peptidic substrate optionally further comprises a P6 amino acid residue selected from Leu, Ile and Val; and

if the peptidic substrate comprises a P2′

amino acid residue, then the peptidic substrate optionally further comprises a P3′

amino acid residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

43. The conjugate of claim 1, wherein:

the therapeutic agent is conjugated directly or via a linker to the C terminus of the peptidic substrate.

44. The conjugate of claim 1, wherein:

the peptidic substrate comprises a cap at the N-terminus.

45. The conjugate of claim 1, wherein the cap is a hydrophilic blocking group.

46. The conjugate of claim 1, wherein the cap is an acyl, sulfonyl or carbamoyl derivative.

47. The conjugate of claim 45, wherein the blocking group is selected from among hydroxylated alkanoyls, polyhydroxylated alkanoyls, polyethylene glycols, glycosylates, sugars and crown ethers.

48. The conjugate of claim 43 that has formula I:

Xⁿ-(P6)_m-(P5)_p-(P4)_l-(P3)_j-(P2)_i-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-(L)_n-Z

or a derivative thereof, wherein;

Z is a therapeutic agent;

L is a linker;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k and r are selected as follows;

u is 0 or 1;

when u is 0, k and r are 0;

when u is 1, k is 0 or 1;

when k is 0, r is 0;

when k is 1, r is 0 or 1;

n is 0 or 1;

Xⁿ is hydrogen, or an acyl, sulfonyl or carbamoyl cap;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gln, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

49. The conjugate of claim 48, wherein P1 is Arg, Lys or an Arg surrogate.

50. The conjugate of claim 1, wherein:

the therapeutic agent is conjugated directly or via a linker to the N terminus of the peptidic substrate.

51. The conjugate of claim 50, wherein:

the C-terminus of the peptidic substrate is a carboxylic acid or a carboxamide derivative.

52. The conjugate of claim 50 that has formula II:

Z-(L)_n-(P6)_m-(P5)_p-(P4)_i-(P3)_j-(P2)_l-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-X^c

or a derivative thereof, wherein;

Z is a therapeutic agent;

L is a linker;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k and r are selected as follows;

u is 0 or 1;

when u is 0, k and r are 0;

when u is 1, k is 0 or 1;

when k is 0, r is 0;

when k is 1, r is 0 or 1;

n is 0 or 1;

X^c, together with the carbonyl group of the amino acid residue to which it is attached, forms a carboxylic acid or a carboxamide group;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gln, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

53. The conjugate of claim 52, wherein P1 is Arg, Lys or an Arg surrogate.

54. The conjugate of claim 1, wherein a first therapeutic agent is attached, optionally via a first linker, to the N-terminus of the peptidic substrate;

and

a second therapeutic agent, which are the same or different from the first therapeutic agent, is attached, optionally via a second linker, which are the same or different from the first linker, to the C-terminus of the peptidic substrate.

55. The conjugate of claim 54 that has formula III:

Z¹-(L¹)_n-(P6)_m-(P5)_p-(P4)_i-(P3)_j-(P2)_l-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-(L²)_v-Z²

or a derivative thereof, wherein;

Z¹ and Z² are each therapeutic agents and are the same or different;

L¹ and L² are each linkers and are the same or different;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k and r are selected as follows;

u is 0 or 1;

when u is 0, k and r are 0;

when u is 1, k is 0 or 1;

when k is 0, r is 0;

when k is 1, r is 0 or 1;

n and v are each independently 0 or 1;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gln, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

56. The conjugate of claim 55, wherein P1 is Arg, Lys or an Arg surrogate.

57. The conjugate of claim 1, selected from:

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     46);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     47);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     48);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     49);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     50);

Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     51);

Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     52);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     53);

Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     54);

Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     55);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     56);

Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

57);

Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     58);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     59);

Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     60);

Ac-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     61);

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     62);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     63);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     64);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     65);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     66);

Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     67);

Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     68);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     69);

Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     70);

Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     71);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     72);

Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     73);

Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO;

     74);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     75);

Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     76); and

Ac-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     77)

pyroGlu-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     78);

CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     79);

N-p-tosyl-GIy-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     80);

BenzoyI-Val-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     81);

CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     82);

N-α

-Z-D-Arg-Gly-Arg-Ala-Ala-(therapeutic agent) in which Z is benzyloxycarbonyl (SEQ ID NO;

     83);

pyroGlu-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     84);

H-D-Ile-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     85);

Cbo-L-(γ

)Glu(α

-t-BuO)-Gly-Arg-Ala-Ala-(therapeutic agent) in which Cbo is carbobenzoxy (SEQ ID NO;

     86);

H-D-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     87);

H-D-Val-Leu-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     88);

Bz-Ile-Glu(γ

-OH)-Gly-Arg-Ala-Ala-(therapeutic agent) in which Bz is benzoyl (SEQ ID NO;

     89);

Bz-Ile-Glu(γ

-OMe)-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     90);

Bz-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     91);

H-D-Phe-Pip-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     92);

H-D-Val-Leu-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     93);

H-D-Nle-HHT-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     94);

Pyr-Arg-Thr-Lys-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     95);

H-Arg-Gln-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     96);

Boc-Gln-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     97);

Z-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     98);

H-D-HHT-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     99);

H-D-CHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     100);

MeSO₂-dPhe-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     101);

δ

-Z-D-Lys-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     102);

CH₃SO₂-D-CHA-But-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     103);

Ac-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     104);

Ac-Arg-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     105);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO;

     106);

Ac-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO;

     107);

Ac-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO;

     108);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Gly-Gly-(therapeutic agent) (SEQ ID NO;

     109);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO;

     110);

Ac-Arg-Arg-Gln-Ser-Arg-Ile-(therapeutic agent) (SEQ ID NO;

     111);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ile-(therapeutic agent) (SEQ ID NO;

     112);

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     113);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     114);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     115);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     116);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     117);

Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     118);

Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

11

     9);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     120);

Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     121);

Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     122);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     123);

Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     124);

Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     125);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     126);

Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     127);

Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     128);

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     129);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     130);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     131);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     132);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     133);

Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     134);

Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     135);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     136);

Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     137);

Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     138);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     139);

Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     140);

Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     141);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     142);

Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     143);

Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     144);

pyroGlu-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     145);

CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     146);

N-p-tosyl-Gly-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     147);

Benzoyl-Val-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     148);

CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     149);

N-α

-Z-D-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     150) (Z=benzyloxycarbonyl);

pyroGlu-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     151);

H-D-Ile-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     152);

Cbo-L-(γ

)Glu(α

-t-BuO)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     153) (Cbo=carbobenzoxy);

H-D-Pro-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     154);

H-D-Val-Leu-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     155);

Bz-Ile-Glu(γ

-OH)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     156) (Bz=benzoyl);

Bz-Ile-Glu(γ

-OMe)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     157);

Benzoyl-Pro-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     158);

H-D-Phe-Pip-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     159);

H-D-Val-Leu-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     160);

H-D-Nle-HHT-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     161);

Pyr-Arg-Thr-Lys-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     162);

H-Arg-Gln-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     163);

Boc-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     164);

Z-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     165);

H-D-HHT-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     166);

H-D-CHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     167);

MeSO₂-dPhe-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     168);

δ

-Z-D-Lys-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     169);

CH₃SO₂-D-CHA-But-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     170);

Ac-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     171);

Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     172);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     173);

Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     174);

Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     175);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     176);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     177);

Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     178);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     179);

Ac-Arg-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     180);

Ac-Arg-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     181);

Ac-Arg-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     182);

Ac-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     183);

Ac-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     184);

Ac-Arg-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     185);

Ac-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     186);

Ac-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     187);

Ac-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     188);

Ac-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     189);

Ac-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     190);

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     191);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     192);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     193);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     194);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     195);

Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     196);

Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     197);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     198);

Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     199);

Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     200);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     201);

Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     202);

Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     203);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     204);

Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     205);

Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     206);

Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     207);

Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     208);

Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     209);

Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     210);

Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     211);

Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     212);

Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     213);

Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     214);

Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     215);

Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     216);

Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     217);

Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     218);

Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     219);

Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     220);

Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     221);

Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     222);

pyroGlu-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     223);

CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     224);

N-p-tosyl-Gly-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     225);

Benzoyl-Val-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     226);

CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     227);

N-α

-Z-D-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     228) (Z=benzyloxycarbonyl);

pyroGlu-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     229);

H-D-Ile-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     230);

Cbo-L-(γ

)Glu(α

-t-BuO)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     231) (Cbo=carbobenzoxy);

H-D-Pro-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     232);

H-D-Val-Leu-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     233);

Bz-Ile-Glu(γ

-OH)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     234) (Bz=benzoyl);

Bz-Ile-Glu(γ

-OMe)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     235);

Benzoyl-Pro-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     236);

H-D-Phe-Pip-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     237);

H-D-Val-Leu-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     238);

H-D-Nle-HHT-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     239);

Pyr-Arg-Thr-Lys-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     240);

H-Arg-Gln-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     241);

Boc-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     242);

Z-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     243);

H-D-HHT-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     244);

H-D-CHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     245);

MeSO₂-dPhe-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     246);

δ

-Z-D-Lys-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     247);

CH₃SO₂-D-CHA-But-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     248);

Ac-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     249);

Ac-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     250);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     251);

Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     252);

Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO;

     253);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     254);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     255);

Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     256);

Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     257);

Ac-Arg-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     258);

Ac-Arg-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     259);

Ac-Arg-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     260);

Ac-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     261);

Ac-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     262);

Ac-Arg-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     263);

Ac-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     264);

Ac-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     265);

Ac-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     266);

Ac-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     267); and

Ac-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO;

     268).

58. The conjugate of claim 35, wherein P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Phe and Val.

59. The conjugate of claim 35, wherein:

P2, P3 and/or P4 is/are selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, GLu, Phe and Val.

60. The conjugate of claim 35, wherein:

P2, P3 and/or P4 is/are selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Tyr, Glu, Leu Phe and Val; and

P1 is any amino acid.

61. The conjugate of claim 60, wherein P1 is a naturally-occurring amino acid.

62. The conjugate of claim 60, wherein P1 is an amimo acid with an aromatic, branched, or branched aromatic side chain.

63. The conjugate of claim 60, wherein P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr.

64. The conjugate of claim 60, wherein P1 is Arg, Lys or an Arg surrogate.

65. The conjugate of claim 1, wherein the protease is located at the cell surface by virtue of a specific binding interaction with a receptor therefor.

66. The conjugate of claim 65, wherein the cell surface protease is urokinase plasminogen activator (u-PA) bound to urokinase plasminogen activator receptor (u-PAR).

67. The conjugate of claim 1, that comprises a peptidic substrate of the formula P6-P5-P4-P3-P2-P1-P1′

-P2′

-P3′

, wherein each of P1, P2, P3, P4, P5, P6, P1′ and

P2′

are selected from residues set forth in FIGS. 1 and 2, and P6, P5, P4, P2′ and

P3′

are optional.

68. The conjugate of claim 67, wherein:

P6 is optional and is selected from L, V, R;

P5 is optional and is selected from R, I, L;

P4 is optional and is selected from G, C, V;

P3 is selected from S, dS, P, A or G;

P2 is selected from A or G;

P1 is R;

P1′

is S, V, M or nL;

P2′

is optional and is selected S, L, A or V; and

P3′

is optional and is L.

70. The conjugate of claim 65, wherein the therapeutic agent is a toxin, a small organic molecule, a nucleic acid, protein therapeutic agents, a cytokine or a growth factor.

71. The conjugate of claim 65, wherein the therapeutic agent is an anti-cancer agent.

72. The conjugate of claim 65, wherein the therapeutic agent is an anti-angiogenic agent.

73. The conjugate of claim 65, wherein the therapeutic agent is selected from abrin, ricin A, pseudomonas exotoxin shiga toxin, diphtheria toxin, a tumor necrosis factor, α

-interferon, γ

-interferon, nerve growth factor, tissue factor and tissue factor variants, FAS-ligand platelet derived growth factor, tissue plasminogen activator, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GMCSF), granulocyte colony stimulating factor (G-CSF), erythropoietin (EPO), nerve growth factor, fibroblast growth factors (FGFs), and epidermal growth factor.

74. The conjugate of claim 65, wherein the therapeutic agent is selected from alkylating agents, toxins, antiproliferative agents, pro-apoptotic agents, pro-coagulants, cytotoxic nucleosides and tubulin binding agents.

75. The conjugate of claim 65, wherein the therapeutic agent is selected from among the following classes of drugs:

a) anthracycline family of drugs,

b) vinca alkaloid drugs,

c) mitomycins,

d) bleomycins,

e) cytotoxic nucleosides,

f) pteridine family of drugs.

g) diynenes,

h) estramustine,

i) cyclophosphamide,

j) taxanes,

k) podophyllotoxins,

l) maytansanoids,

m) epothilones, and

n) combretastatin and analogs,

or pharmaceutically acceptable derivatives thereof.

76. The conjugate of claim 65, wherein the therapeutic agent is selected from among the following drugs:

a) doxorubicin,

b) carminomycin,

c) daunorubicin,

d) aminopterin,

e) methotrexate,

f) methopterin,

g) dichloromethotrexate,

h) mitomycin C,

i) porfiromycin,

j) 5-fluorouracil,

k) 6-mercaptopurine,

l) cytosine arabinoside,

m) podophyllotoxin,

n) etoposide,

o) etoposide phosphate,

p) melphalan,

q) vinblastine,

r) vincristine,

s) leurosidine,

t) vindesine,

u) estramustine,

v) cisplatin,

w) cyclophosphamide,

x) taxol,

y) leurositte,

z) 4-desacetylvinblastine,

aa) epothilone B,

bb) taxotere,

cc) maytansanol,

dd) epothilone A, and

ee) combretastatin and analogs;

or a pharmaceutically acceptable derivative thereof.

77. The conjugate of claim 65, further comprising a linker between the therapeutic agent and the peptidic substrate.

78. The conjugate of claim 65, wherein the linker comprises a carbohydrate, peptide, and/or hydrocarbon core.

79. The conjugate of claim 77, wherein the linker comprises:

a biscarbonyl alkyl diradical whereby an amine moiety on the therapeutic agent is connected with the linker unit to form an amide bond and the amino terminus of the peptidic substrate is connected with the other end of the linker unit also forming an amide bond;

or

a diaminoalkyl diradical linker unit, whereby a carbonyl moiety on the therapeutic agent is covalently attached to one of the amines of the linker unit while the other amine of the linker unit is covalently attached to the C-terminus of the peptidic substrate;

or

is a self-eliminating linker of the following formulae;

where A is NH or O;

D is N(H or alkyl) or O;

R²⁵ is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substituted with 1 or more, such as 1 to 3, substituents selected from, for example, halo, halo alkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)yl groups, halo, pseudohalo, cyano, hydroxy, haloalkyl and polyhaloalkyl, such as, for example, halo lower alkyl, including trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl that optionally is substituted with 1 or more, such as, for example, 1 to 3, substituents selected from, for example, halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl; and

y is an integer from 1 to 3.

80. The conjugate of claim 77, wherein the linker is a diamine comprising a cyclic alkylene moiety.

81. The conjugate of claim 77, wherein the diamine contains a bicycloalkylene moiety.

82. The conjugate of claim 77, wherein the linker selected from 1,4-bis(aminomethyl)cyclohexane, 1,4-bis(aminomethyl)cycloheptane, 1,3-bis(aminomethyl)cyclopentane, 1-amino-4-(aminomethyl)cyclohexane, 1,4-diaminocyclohexane and 1,4-bis(aminomethyl)bicyclo[2.2.2]octane.

83. The conjugate of claim 77, wherein the linker is a 1,ω

-diaminoalkane.

84. The conjugate of claim 77, wherein the linker is a 1,3-diaminopropane.

85. The conjugate of claim 77, wherein the linker is a 1,ω

-dicarbonylalkane.

86. The conjugate of claim 77, wherein the linker is selected from oxalic, malonic, succinic, glutaric, adipic and pivalic acids.

87. The conjugate of claim 1, wherein:

the peptidic substrate comprises a P1-P1′

bond;

the P1-P1′

bond is the site of cleavage by a cell surface protease;

P1 is selected from Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; and

P1′

is Gly, Ser, hSer, Thr, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl.

88. The conjugate of claim 87, further comprising a P2 residue selected from Phe, Ser, Gly, Ala, Ser(OMe), hSer, 1-methylHis, 3-methylHis, His, nVal, nLeu, Abu, (hS)Gly, Thr, Aib, CHA and Tyr.

89. The conjugate of claim 88, further comprising a P3 residue selected from Arg, Lys, Gin, Quat, Arg surrogates, Ser, Thr, hSer, dSer, Pro, (hS)Gly, Tyr, 4,4-dimethylThr, Asn, Met(O₂), Quat², Quat³, Quat⁴ and Quat⁵.

90. The conjugate of claim 89, further comprising a P4 residue selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β

-Ala, Cys(Me), Gln, t-butylGly and nVal.

91. The conjugate of claim 90, further comprising a P5 residue selected from Ile, Arg and Arg surrogates.

92. The conjugate of claim 91, further comprising a P6 residue selected from Val, Leu, Ile and Val.

93. The conjugate of claim 87, further comprising a P2′

residue selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, hCHA, CHA, hexylGly, allylGly and Phe.

94. The conjugate of claim 93, further comprising a P3′

residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly.

95. The conjugate of claim 94, further comprising a P4′

residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly.

96. The conjugate of claim 95, wherein P4′

is Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

97. The conjugate of claim 96, wherein P4′

is Leu.

98. The conjugate of claim 1, wherein:

the peptidic substrate comprises a 5-mer that has the formula;

P4-P3-P2-P1-P1′

, wherein;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P2 is selected from Phe, Ser, Gly, Ala, Ser(OMe), hSer, 1-methylHis, 3-methylHis, His, nVal, nLeu, Abu, (hS)Gly, Thr, Aib, CHA and Tyr;

P3 is selected from Arg, Lys, Gln, Quat, Arg surrogates, Ser, Thr, hSer, dSer, Pro, (hS)Gly, Tyr, 4,4-dimethylThr, Asn, Met(O₂), Quat², Quat³, Quat⁴ and Quat⁵;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β

-Ala, Cys(Me), Gln, t-butylGly and nVal; and

P1′

is Gly, Ser, hSer, Thr, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl.

99. The conjugate of claim 40, wherein:

the peptidic substrate optionally further comprises one or more of a P5 or P2′

amino acid residue, wherein;

P5 is Ile, Arg or an Arg surrogate; and

P2′

is selected from among Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, hCHA, CHA, hexylGly, allylGly and Phe.

100. The conjugate of claim 41, wherein:

if the peptidic substrate comprises a P5 amino acid residue, then the peptidic substrate optionally further comprises a P6 amino acid residue selected from Arg, Leu, Ile and Val; and

if the peptidic substrate comprises a P2′

amino acid residue, then the peptidic substrate optionally further comprises a P3′

amino acid residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly; and

if the peptidic substrate comprises a P3′

amino acid residue, then the peptidic substrate optionally further comprises a P4′

amino acid residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly.

101. The conjugate of claim 43 that has formula IV:

Xⁿ-(P6)_m-(P5)_p-(P4)_i-(P3)_j-(P2)_l-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-(P4′

)_s-(L)_n-Z

or a derivative thereof, wherein;

Z is a therapeutic agent;

L is a linker;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k, r and s are selected as follows;

u is 0 or 1;

when u is 0, k, r and s are 0;

when u is 1, k is 0 or 1;

when k is 0, r and s are 0;

when k is 1, r is 0 or 1;

when r is 0, s is 0;

when r is 1, s is 0 or 1;

n is 0 or 1;

Xⁿ is hydrogen, or an acyl, sulfonyl or carbamoyl cap;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gin, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl;

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P4′

is selected from Gly, Ser, Ala, Leu, ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

102. The conjugate of claim 50 that has formula V:

Z-(L)_n-(P6)_m-(P5)_p-(P4)_i-(P3)_j-(P2)_l-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-(P4′

)_s-X^c

or a derivative thereof, wherein;

Z is a therapeutic agent;

L is a linker;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k, r and s are selected as follows;

u is 0 or 1;

when u is 0, k, r and s are 0;

when u is 1, k is 0 or 1;

when k is 0, r and s are 0;

when k is 1, r is 0 or 1;

when r is 0, s is 0;

when r is 1, s is 0 or 1;

n is 0 or 1;

X^c, together with the carbonyl group of the amino acid residue to which it is attached, forms a carboxylic acid or a carboxamide group;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gln, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl;

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P4′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

103. The conjugate of claim 54 that has formula VI:

Z¹-(L¹)_n-(P6)_m-(P5)_p-(P4)_i-(P3)_j-(P2)_l-P1-(P1′

)_u-(P2′

)_k-(P3′

)_r-(P4′

)_s-(L²)_v-Z²

or a derivative thereof, wherein;

Z¹ and Z² are each therapeutic agents and are the same or different;

L¹ and L² are each linkers and are the same or different;

l, j, i, p and m are selected as follows;

l is 0 or 1;

when l is 0, j, i, p and m are 0;

when l is 1, j is 0 or 1;

when j is 0, i, p and m are 0;

when j is 1, i is 0 or 1;

when i is 0, p and m are 0;

when i is 1, p is 0 or 1;

when p is 0, m is 0;

when p is 1, m is 0 or 1;

u, k, r and s are selected as follows;

u is 0 or 1;

when u is 0, k, r and s are 0;

when u is 1, k is 0 or 1;

when k is 0, r and s are 0;

when k is 1, r is 0 or 1;

when r is 0, s is 0;

when r is 1, s is 0 or 1;

n and v are each independently 0 or 1;

P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;

P1′

is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl;

P2 is selected from Phe, Ser, Gly and Ala;

P3 is selected from Arg, Lys, Gin, Ser, Quat and Arg surrogates;

P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val;

P5 is selected from Arg and Arg surrogates;

P6 is selected from Leu, Ile and Val;

P2′

is selected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl;

P3′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and

P4′

is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.

104. The conjugate of claim 1, selected from:

Ac-R-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     491);

Ac-R-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     492);

Ac-R-Q-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     493);

Ac-R-Q-G-R-S-nV-(therapeutic agent) (SEQ ID NO;

     494);

Ac-R-Q-G-R-S-F-(therapeutic agent) (SEQ ID NO;

     495);

Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     496);

Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     497);

Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO;

     498);

Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO;

     499);

Ac-R-Q-G-R-A-nV-(therapeutic agent) (SEQ ID NO;

     500);

Ac-R-Q-G-R-A-Cha-(therapeutic agent) (SEQ ID NO;

     501);

Ac-R-Q-G-R-A-F-(therapeutic agent) (SEQ ID NO;

     502);

Ac-R-N-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     503);

Ac-R-N-G-R-A-nL-(therapeutic agent) (SEQ ID NO;

     504);

Ac-R-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     505);

Ac-R-Q-A-R-S-nL-(therapeutic agent) (SEQ ID NO;

     506);

Ac-R-Q-A-R-S-nV-(therapeutic agent) (SEQ ID NO;

     507);

Ac-R-Q-A-A-S-Cha-(therapeutic agent) (SEQ ID NO;

     508);

Ac-R-Q-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     509);

Ac-R-Q-A-R-T-nL-(therapeutic agent) (SEQ ID NO;

     510);

Ac-R-Q-A-R-A-L-(therapeutic agent) (SEQ ID NO;

     511);

Ac-R-Q-A-R-A-nL-(therapeutic agent) (SEQ ID NO;

     512);

Ac-R-Q-A-R-A-nV-(therapeutic agent) (SEQ ID NO;

     513);

Ac-R-Q-A-R-A-Cha-(therapeutic agent) (SEQ ID NO;

     514);

Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     515);

Ac-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO;

     516);

Ac-R-Q-S-R-A-nL-(therapeutic agent) (SEQ ID NO;

     517);

Ac-R-Q-S-R-A-L-(therapeutic agent) (SEQ ID NO;

     518);

Ac-R-Q-S-R-A-nV-(therapeutic agent) (SEQ ID NO;

     519);

Ac-R-Q-S-R-A-Cha-(therapeutic agent) (SEQ ID NO;

     520);

Ac-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     521);

Ac-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     522);

Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO;

     523);

Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO;

     524);

Ac-R-Q-S-R-S-nV-(therapeutic agent) (SEQ ID NO;

     525);

Ac-R-Q-S-R-S-allylG-(therapeutic agent) (SEQ ID NO;

     526);

Ac-R-Q-S-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     527);

Ac-R-Q-S-R-T-nL-(therapeutic agent) (SEQ ID NO;

     528);

Ac-R-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     529);

Ac-R-Q-T-R-S-L-(therapeutic agent) (SEQ ID NO;

     530);

Ac-R-N-S-R-S-nL-(therapeutic agent) (SEQ ID NO;

     531);

Ac-R-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO;

     532);

Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO;

     534);

Ac-R-Q-F-R-S-nV-(therapeutic agent) (SEQ ID NO;

     535);

Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO;

     536);

Ac-R-Q-F-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     537);

Ac-R-Q-F-R-A-L-(therapeutic agent) (SEQ ID NO;

     538);

Ac-R-Q-F-R-A-nL-(therapeutic agent) (SEQ ID NO;

     539);

Ac-R-Q-F-R-A-nV-(therapeutic agent) (SEQ ID NO;

     540);

Ac-R-Q-F-R-A-Cha-(therapeutic agent) (SEQ ID NO;

     541);

Ac-Q-S-R-S-S-nL-(therapeutic agent) (SEQ ID NO;

     542);

MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     483);

MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     484);

MeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     485);

MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     486);

MeOCO-Quat5-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     487);

MeOCO-Quat2-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     488);

MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     489);

MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     490);

Ac-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     445);

Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     446);

Ac-Q-G-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     447);

Ac-N-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     448);

Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO;

     449);

Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO;

     450);

Ac-Q-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     451);

Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO;

     452);

Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO;

     453);

Ac-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     454);

Ac-Q-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     455);

Ac-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     456);

Ac-Q-S-R-S-S-nV-(therapeutic agent) (SEQ ID NO;

     457);

Ac-Q-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     458);

Ac-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     459);

Ac-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     460);

Ac-Q-Aib-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     461);

Ac-Q-Aib-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     462);

Ac-Q-Abu-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     463);

Ac-Q-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     464);

Ac-Q-Cha-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     465);

Ac-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO;

     466);

Ac-Q-F-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     467);

Ac-Q-Y-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     468);

Ac-R-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     469);

Ac-R-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     470);

Ac-R-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     471);

Ac-R-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     472);

Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     473);

Ac-R-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     474);

Ac-R-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     475);

Ac-R-S-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     476);

Ac-R-S-RS-Cha-(therapeutic agent) (SEQ ID NO;

     477);

Ac-R-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     478);

Ac-R-F-R-S-L-(therapeutic agent) (SEQ ID NO;

     479);

Ac-R-F-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     480);

Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     481);

Ac-M(O2)-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     482);

Ac-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     105);

Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO;

     610);

Ac-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     543);

Ac-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     544);

Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     545);

Ac-R-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     546);

Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO;

     547);

Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     548);

Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     549);

Ac-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO;

     108);

Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO;

     111);

Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     106);

Ac-L-R-R-Q-S-R-G-G-(therapeutic agent) (SEQ ID NO;

     109);

Ac-L-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO;

     110);

Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO;

     112);

Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO;

     611);

Ac-L-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     550);

Ac-L-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO;

     551);

Ac-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     362);

Ac-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     363);

Ac-S-G-R-S-S-S-L-(therapeutic agent) (SEQ ID NO;

     364);

Ac-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     365);

Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO;

     366);

isomer 1

Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO;

     367);

isomer 2

Ac-S-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO;

     368);

Ac-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     369);

Ac-S-G-R-S-hCha-(therapeutic agent) (SEQ ID NO;

     370);

Ac-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     371);

Ac-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     372);

Ac-S-S-R-S-nL-(therapeutic agent) (SEQ ID NO;

     373);

Ac-T-G-R-S-Abu-(therapeutic agent) (SEQ ID NO;

     374);

Ac-T-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     375);

Ac-T-G-R-S-nV-(therapeutic agent) (SEQ ID NO;

     376);

Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     377);

Ac-T-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO;

     378);

Ac-T-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     379);

Ac-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO;

     380);

Ac-T-G-R-T-Abu-(therapeutic agent) (SEQ ID NO;

     381);

Ac-T-G-R-hS-nL-(therapeutic agent) (SEQ ID NO;

     382);

Ac-T-G-R-Abu-nL-(therapeutic agent) (SEQ ID NO;

     383);

Ac-T-G-R-Abu-nV-(therapeutic agent) (SEQ ID NO;

     384);

Ac-T-G-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO;

     385);

Ac-T-G-F(Gn)-S-Cha-(therapeutic agent) (SEQ ID NO;

     386);

Ac-T-G-F(Gn)-Abu-nV-(therapeutic agent) (SEQ ID NO;

     387);

Ac-T-G-K(alloc)-S-nL-(therapeutic agent) (SEQ ID NO;

     388);

Ac-T-G-K-S-nL-(therapeutic agent) (SEQ ID NO;

     389);

Ac-T-G-hR-S-nL-(therapeutic agent) (SEQ ID NO;

     390);

Ac-(hS)G-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     391);

MeOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     392);

PhSO2-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     393);

MeOEtCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     394);

Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     395);

4-oxo-Pentanoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     396);

3,4-MethyldioxyPhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     397);

2-PyridylAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     398);

PhOAc-Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     399);

L-3-PhLactyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     400);

MeOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     401);

PhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     402);

MeOEtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     403);

MeOEtOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     404);

HOOCButa-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     405);

Z-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     406);

EtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     407);

β

A-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     408);

Pent-4-ynoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     409);

NapAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     410);

iBoc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     411);

HOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     412);

MeSucc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     413);

N,N-diMeGly-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     414);

Succ-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     415);

HCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     416);

Ac-T-A-R-S-nL-(therapeutic agent) (SEQ ID NO;

     417);

Ac-T-A-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO;

     418);

Ac-T-A-R-Abu-nV-(therapeutic agent) (SEQ ID NO;

     419);

Ac-T-A-R-S-Abu-(therapeutic agent) (SEQ ID NO;

     420);

Ac-T-A-R-T-Abu-(therapeutic agent) (SEQ ID NO;

     421);

Ac-T-S(O-Me)-R-S-nL-(therapeutic agent) (SEQ ID NO;

     422);

Ac-T-hS-R-S-nL-(therapeutic agent) (SEQ ID NO;

     423);

Ac-T-(1-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO;

     424);

Ac-T-(3-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO;

     425);

Ac-T-H-R-S-nL-(therapeutic agent) (SEQ ID NO;

     426);

Ac-T-Sar-R-S-nL-(therapeutic agent) (SEQ ID NO;

     427);

Ac-T-nV-R-S-nL-(therapeutic agent) (SEQ ID NO;

     428);

Ac-T-nL-R-S-nL-(therapeutic agent) (SEQ ID NO;

     429);

Ac-T-A-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     430);

Ac-T-Abu-R-S-nL-(therapeutic agent) (SEQ ID NO;

     431);

Ac-4,4diMeThr-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     432);

Ac-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     433);

Ac-hS-G-R-hS-Cha-(therapeutic agent) (SEQ ID NO;

     434);

Ac-hS-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     435);

Ac-hS-G-R-T-Cha-(therapeutic agent) (SEQ ID NO;

     436);

Ac-hS-A-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     437);

Ac-N-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     438);

Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     439);

Ac-Y-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     440);

Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO;

     441);

Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO;

     442);

Ac-L-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO;

     573);

Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     342);

Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     343);

Ac-L-R-G-S-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO;

     344);

Ac-L-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     345);

Ac-L-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO;

     574);

Ac-L-R-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     346);

Ac-L-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     347);

Ac-L-R-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     348);

Ac-L-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO;

     349);

Ac-L-R-G-S-A-R-S-S-nL-(therapeutic agent) (SEQ ID NO;

     350);

Ac-V-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     351);

Ac-V-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     352);

Ac-V-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     353);

Ac-V-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO;

     354);

Ac-V-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO;

     355);

Ac-V-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO;

     356);

Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     357);

Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     358);

Ac-V-I-V-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     359);

Ac-R-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO;

     360);

Ac-R-R-nV-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     361);

Ac-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO;

     309);

Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO;

     310);

Ac-R-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     311);

Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     312);

Ac-R-G-S-G-R--S-nL-(therapeutic agent) (SEQ ID NO;

     313);

Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO;

     314);

Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     315);

Ac-R-G-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     316);

Ac-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     317);

Ac-R-G-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO;

     318);

Ac-R-G-S-A-R-S-S-(therapeutic agent) (SEQ ID NO;

     319);

Ac-R-G-S-A-R-S-nV-(therapeutic agent) (SEQ ID NO;

     320);

Ac-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO;

     321);

Ac-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     322);

Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO;

     323);

Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO;

     324);

Ac-R-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     325);

Ac-R-L-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     326);

Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     327);

Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     328);

Ac-R-nL-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     329);

Ac-R-G(tBu)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     330);

Ac-R-L-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     331);

Ac-R-V-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     332);

Ac-R-nL-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     333);

Ac-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     334);

Ac-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     335);

Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     336);

Ac-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO;

     337);

Ac-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO;

     338);

Ac-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     339);

Ac-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO;

     340);

Ac-I-V-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     341);

Ac-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO;

     585);

Ac-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     277);

Ac-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     278);

Ac-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     279);

Ac-G-S-G-R-L-(therapeutic agent) (SEQ ID NO;

     280);

Ac-G-S-G-(4-guan)Phg-S-L-(therapeutic agent) (SEQ ID NO;

     281);

Ac-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     282);

Ac-G-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     283);

Ac-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     284);

Ac-G-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     285);

Succ-bA-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     286);

Ac-G-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO;

     287);

Ac-G-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO;

     288);

Ac-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO;

     289);

Ac-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     290);

Ac-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO;

     291);

Ac-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     292);

Ac-G-S-A-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     293);

Ac-V-S-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     294);

Ac-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     295);

Ac-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     296);

Ac-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     297);

Ac-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO;

     298);

Ac-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO;

     299);

Ac-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO;

     300);

Ac-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     301);

Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO;

     302);

Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO;

     303);

Ac-C(Me)-P-G-R-A-L-(therapeutic agent) (SEQ ID NO;

     304);

Ac-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     305);

Ac-C(Me)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     306);

Ac-C(Me)-P-A-R-A-S-L-(therapeutic agent) (SEQ ID NO;

     307);

Ac-G(tBu)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     308);

Ac-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     552);

Ac-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO;

     553);

Ac-Q-S-R-S-G-(therapeutic agent) (SEQ ID NO;

     554);

Ac-R-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     555);

Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     556);

Ac-R-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO;

     557);

Ac-R-Q-S-R-S-A-A-(therapeutic agent) (SEQ ID NO;

     558);

Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO;

     559);

Ac-S-G-R-A-A-(therapeutic agent) (SEQ ID NO;

     560);

Ac-S-G-R-S-A-(therapeutic agent) (SEQ ID NO;

     561);

Ac-S-G-R-S-S-A-(therapeutic agent) (SEQ ID NO;

     562);

Ac-S-G-R-A-S-A-(therapeutic agent) (SEQ ID NO;

     563);

Ac-S-G-R-S-G-(therapeutic agent) (SEQ ID NO;

     564);

Ac-S-G-R-S-S-G-(therapeutic agent) (SEQ ID NO;

     565);

Ac-S-G-R-S-G-A-(therapeutic agent) (SEQ ID NO;

     566);

Ac-S-G-R-S-G-G-(therapeutic agent) (SEQ ID NO;

     567);

Ac-G-T-G-R-S-G-G-(therapeutic agent) (SEQ ID NO;

     568);

Ac-G-S-G-R-S-G-G-(therapeutic agent) (SEQ ID NO;

     243)

Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO;

     597);

MeSO2-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO;

     598);

Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO;

     599);

Ac-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO;

     600);

Ac-dA(Chx)-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     601);

Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     602);

MeOCO-dhF-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     603);

MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     604);

Ac-dCha-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO;

     605);

Ac-dCha-Abu-R-S-S-A-(therapeutic agent) (SEQ ID NO;

     606);

MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     607);

MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     608); and

MeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO;

     609).

105. The conjugate of claim 35, wherein P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β

-Ala, Cys(Me), Gln, t-butylGly and nVal.

106. The conjugate of claim 1, that comprises a peptidic substrate of the formula P6-P5-P4-P3-P2-P1-P1′

-P2′

-P3′

-P4′

, wherein each of P1, P2, P3, P4, P5, P6, P1′ and

P2′

are selected from residues set forth in FIGS. 1 and 2, and P6, P5, P4, P2′

, P3′ and

P4′

are optional.

107. The conjugate of claim 67, wherein:

P6 is optional and is selected from L, V, R;

P5 is optional and is selected from R, I, L;

P4 is optional and is selected from G, C, V;

P3 is selected from S, dS, P, A or G;

P2 is selected from A or G;

P1 is R;

P1′

is S, V, M or nL;

P2′

is optional and is selected S, L, A or V;

P3′

is optional and is L; and

P4′

is optional and is L.

112. The conjugate of claim 67, wherein:

P6 is optional and is selected from L, V, R;

P5 is optional and is selected from R, I, L;

P4 is optional and is selected from G, C, V;

P3 is selected from S, dS, P, A or G;

P2 is selected from A or G;

P1 is R;

P1′

is T, Abu, hS, nV or A;

P2′

is optional and is selected S, L, A or V;

P3′

is optional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu; and

P4′

is optional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu.

113. The conjugate of claim 67, wherein:

P6 is optional and is selected from L, V, R;

P5 is optional and is selected from R, I, L;

P4 is optional and is selected from G, C, V;

P3 is selected from S, dS, P, A or G;

P2 is selected from A or G;

P1 is R;

P1′

is S, G or A;

P2′

is optional and is selected G or A;

P3′

is optional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu; and

P4′

is optional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu.

114. The conjugate of claim 1, wherein the therapeutic agent is taxol.

115. The conjugate of claim 1, wherein the therapeutic agent is doxorubicin.

116. A method of treatment of a disease, comprising administering a conjugate of claim 1 to a subject, wherein the disease is a cell-surface protease-associated disease.

117. The method of claim 116, wherein the disease is selected from the group consisting of autoimmune disesases, inflammatory diseases, infectious diseases and endocrine diseases.

118. The method of claim 116, wherein the disease is a proliferative disease.

122. The method of claim 114, wherein the subject is a mammal.

124. The method of claim 118, wherein the disease is cancer.

125. The method of claim 118, wherein the disease is selected from ocular disorders, cardiovascular disorders, chronic inflammatory diseases, wounds, circulatory disorders, dermatological disorders and cancer.

126. The method of claim 118, wherein the disease is selected from rheumatoid arthritis, psoriasis, diabetic retinopathies, recurrence of pterygii, scarring from excimer laser surgery, scarring from glaucoma filtering surgery, macular degeneration anterior eye, crest syndromes, solid neoplasms and vascular tumors.

127. The method of claim 118, wherein the disease is selected from lung cancer, colon cancer, pancreatic cancer, esophageal cancer, breast cancer, ovarian cancer, prostate cancer, melanoma and Kaposi'"'"'s sarcoma.

128. The method of claim 116, wherein the therapeutic agent is taxol.

129. The method of claim 116, wherein the therapeutic agent is doxorubicin.

130. A pharmaceutical composition, comprising the conjugate of claim 1 or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.

131. The pharmaceutical composition of claim 130 that is formulated for single dosage administration.

132. An article of manufacture, comprising packaging material, the conjugate of claim 1, or a pharmaceutically acceptable derivative thereof, contained within packaging material, which is used for treatment, prevention or amelioration of one or more symptoms associated with cell-surface protease-associated diseases or disorders, and a label that indicates that the conjugate or pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of one or more symptoms associated with cell-surface protease-associated diseases or disorders.

133. A method of preparing a conjugate of claim 1, comprising:

a) synthesizing the peptidic substrate;

b) optionally capping the peptidic substrate on either the N-terminus or the C-terminus;

c) optionally linking the non-capped terminus of the peptidic substrate to a linker;

d) coupling the peptidic substrate to a therapeutic agent, optionally via the linker, to form a conjugate; and

e) optionally, deprotecting the conjugate, if protected.

134. The method of claim 133, wherein, prior to step a), the method comprises a step of identifying a peptidic substrate for the protease.

69. A conjugate selected from among those set forth in FIGS. 1-5, wherein the therapeutic agent doxorubicin (Dox) or taxol (Tax) optionally is replaced with any therapeutic agent.

108. A conjugate, comprising a therapeutic agent and a nucleic acid substrate linked thereto via a peptidic linker, wherein the peptidic linker is proteolytically cleaved by a cell surface protease or a soluble, released or shed form thereof, to liberate the therapeutic agent, wherein the conjugate is not substantially cleaved by plasmin or prostate specific antigen (PSA).

109. The conjugate of claim 108, wherein the nucleic acid is DNA.

110. The conjugate of claim 108, wherein the nucleic acid is RNA.

111. The conjugate of claim 108, wherein the nucleic acid is double-stranded RNA.

119. A method of treatment of a cell-surface protease-associated disease, comprising administering a conjugate, comprising a therapeutic agent and a peptidic substrate linked thereto optionally via a linker, wherein the peptidic substrate is proteolytically cleaved by a cell surface protease or a soluble, released or shed form thereof to liberate the therapeutic agent, to a subject exhibiting symptoms of a cell-surface protease-associated disorder.

120. The method of claim 119, wherein the disease is selected from the group consisting of autoimmune disesases, inflammatory diseases, infectious diseases and endocrine diseases.

121. The method of claim 119, wherein the disease is a proliferative disease.

123. The method of claim 120, wherein the mammal is a human.

135. A method, comprising:

a) selecting a disease;

b) identifying a cell involved in the disease process or a cell in the vicinity of the cell involved in the disease process; and

c) identifying a cell surface protease on the cell, thereby identifying proteases to target conjugates for treatment of diseases.

136. The method of claim 135, further comprising preparing a conjugate that targets the protease.