Toxin peptide therapeutic agents

• US 20070071764A1
• Filed: 04/17/2006
• Published: 03/29/2007
• Est. Priority Date: 04/22/2005
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Sullivan, John, Gegg, Colin, Walker, Kenneth, Miranda, Leslie, Nguyen, Hung, Hu, Shaw-Fen, McGivern, Joseph, McDonough, Stefan
• Granted Patent: US 7,833,979 B2
• Time in Patent Office: Days
• US Class Current: 424/178.100
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/43504 from invertebrates
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/55 containing a fusion with a toxin, e.g. diphteria toxin

Abstract

Disclosed is a composition of matter of the formula
(X¹)_a—(F¹)_d—(X²)_b—(F²)_e—(X³)_c  (I)
and multimers thereof, in which F¹ and F² are half-life extending moieties, and d and e are each independently 0 or 1, provided that at least one of d and e is 1; X¹, X², and X³ are each independently -(L)_f-P-(L)_g-, and f and g are each independently 0 or 1; P is a toxin peptide of no more than about 80 amino acid residues in length, comprising at least two intrapeptide disulfide bonds; L is an optional linker; and a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1. Linkage to the half-life extending moiety or moieties increases the in vivo half-life of the toxin peptide, which otherwise would be quickly degraded. A pharmaceutical composition comprises the composition and a pharmaceutically acceptable carrier. Also disclosed are a DNA encoding the inventive composition of matter, an expression vector comprising the DNA, and a host cell comprising the expression vector. Methods of treating an autoimmune disorder, such as, but not limited to, multiple sclerosis, type 1 diabetes, psoriasis, inflammatory bowel disease, contact-mediated dermatitis, rheumatoid arthritis, psoriatic arthritis, asthma, allergy, restinosis, systemic sclerosis, fibrosis, scleroderma, glomerulonephritis, Sjogren syndrome, inflammatory bone resorption, transplant rejection, graft-versus-host disease, and lupus and of preventing or mitigating a relapse of a symptom of multiple sclerosis are also disclosed.

Claims

1. A composition of matter of the formula

(X¹)_a—

(F¹)_d—

(X²)_b—

(F²)_e—

(X³)_c

and multimers thereof, wherein;

F¹ and F² are half-life extending moieties, and d and e are each independently 0 or 1, provided that at least one of d and e is 1;

X¹, X², and X³ are each independently -(L)_f-P-(L)_g-, and f and g are each independently 0 or 1;

P is a toxin peptide of no more than about 80 amino acid residues in length, comprising at least two intrapeptide disulfide bonds;

L is a linker; and

a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1.

2. The composition of matter of claim 1 of the formula P-(L)_g-F¹.

3. The composition of matter of claim 1 of the formula F¹-(L)_f-P.

4. The composition of matter of claim 1 of the formula P-(L)_g-F¹-(L)_f-P.

5. The composition of matter of claim 1 of the formula F¹-(L)_f-P-(L)_g-F².

6. The composition of matter of claim 1 of the formula F¹-(L)_f-P-(L)_g-F²-(L)_f-P.

7. The composition of matter of claim 1 of the formula F¹—

F²-(L)_f-P

8. The composition of matter of claim 1 of the formula P-(L)_g-F¹—

F².

9. The composition of matter of claim 1 of the formula P-(L)_g-F¹—

F²-(L)_f-P.

10. The composition of matter of claim 1, wherein F¹ or F², or both is a polyethylene glycol, a copolymer of ethylene glycol, a polypropylene glycol, a copolymer of propylene glycol, a carboxymethylcellulose, a polyvinyl pyrrolidone, a poly-1,3-dioxolane, a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid, a dextran n-vinyl pyrrolidone, a poly n-vinyl pyrrolidone, a propylene glycol homopolymer, a propylene oxide polymer, an ethylene oxide polymer, a polyoxyethylated polyol, a polyvinyl alcohol, a linear or branched glycosylated chain, a polyacetal, a long chain fatty acid, a long chain hydrophobic aliphatic group, an immunoglobulin F_c domain or portion thereof, a CH2 domain of Fc, an Fc domain loop, an albumin, an albumin-binding protein, a transthyretin, a thyroxine-binding globulin, or a ligand that has an affinity for a long half-life serum protein, said ligand being selected from the group consisting of peptide ligands and small molecule ligands;

or a combination of any of these members.

11. The composition of matter of claim 1 wherein F¹ or F², or both, comprises a human IgG Fc domain or a portion thereof.

12. The composition of matter of claim 11, wherein the human IgG Fc domain comprises a human IgG1 Fc domain.

13. The composition of matter of claim 11, wherein the human IgG Fc domain comprises a human IgG2 Fc domain.

14. The composition of matter of claim 1, wherein F¹ and F² are different half-life extending moieties.

15. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a sequence selected from the group consisting of SEQ ID NOS:

2, 4, 70, 71, 72, 74, 75, 76, 1340 through 1342, and 1359 through 1363 as set forth in (FIGS. 3, 4, 11A-C, 12A-C, and 12E-F).

16. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a human serum albumin protein domain.

17. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a transthyretin protein domain.

18. The composition of matter of claim 1, wherein F¹ or F², or both, comprises a biologically suitable polymer or copolymer.

19. The composition of matter of claim 18, wherein the biologically suitable polymer is polyethylene glycol (PEG).

20. The composition of matter of claim 19, wherein the PEG is selected from the group consisting of 5 kD and 20 kD PEG.

21. The composition of matter of any of claims 5, 6, 8, or 9, wherein F¹ is an human IgG Fc domain or HSA, and F² is PEG.

22. The composition of matter of any of claims 5, 6, 7 or 9, wherein F² is an human IgG Fc domain or HSA and F¹ is PEG.

23. The composition of matter of claim 1, further comprising one or more PEG moieties conjugated to a non-PEG F¹ or non-PEG F², or to P, or to any combination of any of these.

24. The composition of matter of claim 1, in which the toxin peptide is inserted into a human IgG1 Fc domain loop.

25. The composition of claim 1 wherein at least one P comprises a Kv1.3 antagonist peptide.

26. The composition of matter of claim 25, wherein the Kv1.3 antagonist peptide is selected from the group consisting of ShK, HmK, MgTx, AgTx1, AgTx2, HsTx1, OSK1, Anuroctoxin, Noxiustoxin, Hongotoxin, HsTx1, ChTx, Titystoxin, BgK, BmKTX, BmTx, Tc30, Tc32, Pi1, Pi2, and Pi3 toxin peptide, or an analog of any of these.

27. The composition of matter of claim 25, wherein the Kv1.3 antagonist peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

21, 17, 18, 19, 61, 23, 85, 25, 62, 30, 27, 36, 86, 9, 26, 40, 87, and 13 as set forth in Table 1.

28. The composition of matter of claim 1, wherein at least one P comprises an ShK peptide or an ShK peptide analog.

29. The composition of matter of claim 28, wherein the ShK peptide or ShK peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

5, 88 through 200, 548 through 561, 884 through 950, and 1295 through 1300 as set forth in Table 2.

30. The composition of matter of claim 1, wherein at least one P comprises an HmK peptide, a BgK peptide, an AeK peptide, or an AsKS peptide, or a peptide analog of any of these.

31. The composition of matter of claim 30, wherein the HmK peptide, BgK peptide, AeK peptide, or AsKS peptide, or peptide analog, comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

6 through 9, 201 through 241 as set forth in Table 3.

32. The composition of matter of claim 1, wherein at least one P comprises a MgTx peptide or MgTx peptide analog.

33. The composition of matter of claim 32, wherein the MgTx peptide or MgTx peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

28 and 242 through 260 as set forth in Table 4.

34. The composition of matter of claim 1, wherein at least one P comprises an AgTx2 peptide or AgTx2 peptide analog.

35. The composition of matter of claim 34, wherein the AgTx2 peptide or AgTx2 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

23 and 261 through 275 as set forth in Table 5.

36. The composition of matter of claim 1, wherein at least one P comprises an HsTx1 peptide or HsTx1 peptide analog.

37. The composition of matter of claim 36, wherein the HsTx1 peptide or HsTx1 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

61 and 276 through 293 as set forth in Table 6.

38. The composition of matter of claim 1, wherein at least one P comprises an OSK1 peptide or OSK1 peptide analog.

39. The composition of matter of claim 38, wherein the OSK1 peptide or OSK1 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

25, 294 through 298, 562 through 636, 980 through 1274, 1303, and 1308 as set forth in Table 7.

40. The composition of matter of claim 1 wherein at least one P comprises a Pi2 peptide or Pi2 peptide analog.

41. The composition of matter of claim 40, wherein the Pi2 peptide or Pi2 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

17 and 299 through 315 as set forth in Table 8.

42. The composition of matter of claim 1, wherein at least one P comprises an AnTx peptide or AnTx peptide analog.

43. The composition of matter of claim 42, wherein the AnTx peptide or AnTx peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

62 and 316 through 318 as set forth in Table 9.

44. The composition of matter of claim 1, wherein at least one P comprises a NTX peptide or NTX peptide analog.

45. The composition of matter of claim 44, wherein the NTX peptide or NTX peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

30 and 319 through 325 as set forth in Table 10.

46. The composition of matter of claim 1 wherein at least one P comprises a KTX1 peptide or KTX1 peptide analog.

47. The composition of matter of claim 46, wherein the KTX1 peptide or KTX1 analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

24 and 326 through 328 as set forth in Table 11.

48. The composition of matter of claim 1, wherein at least one P comprises an IKCa1 antagonist peptide.

49. The composition of matter of claim 48, wherein the IKCa1 antagonist peptide comprises a MTx peptide, a ChTx peptide, or a peptide analog of either of these.

50. The composition of matter of claim 49, wherein the MTx peptide, ChTx peptide, or peptide analog of either of these, comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

20, 36, and 329 as set forth in Table 12.

51. The composition of matter of claim 1, wherein at least one P comprises an MTX peptide or MTX peptide analog.

52. The composition of matter of claim 51, wherein the MTX peptide or MTX peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

20, 330 through 343, and 1301, 1302, 1304 through 1307, 1309, 1311, 1312, and 1315 through 1336 as set forth in Table 13.

53. The composition of matter of claim 1, wherein at least one P comprises a ChTx peptide or ChTx peptide analog.

54. The composition of matter of claim 53, wherein the ChTx peptide or ChTx peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

36, 59, 344 through 346, and 1369 through 1390 as set forth in Table 14.

55. The composition of matter of claim 1, wherein at least one P comprises a SKCa antagonist peptide.

56. The composition of matter of claim 55, wherein the SKCa antagonist peptide comprises an apamin peptide, a ScyTx peptide, a BmP05 peptide, a P05 peptide, a tamapin peptide, a P01 peptide, or a TsK peptide, or a peptide analog of any of these.

57. The composition of matter of claim 55, wherein the SKCa antagonist peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

16, 47, 50 through 53, and 68 as set forth in Table 15.

58. The composition of matter of claim 1, wherein at least one P comprises an apamin peptide or apamin peptide analog.

59. The composition of matter of claim 58, wherein the apamin peptide or apamin peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

68 and 348 through 353 as set forth in Table 16.

60. The composition of matter of claim 56, wherein the ScyTx peptide, tamapin peptide, or peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

51, 53 and 354 through 356 as set forth in Table 17.

61. The composition of matter of claim 1, wherein at least one P comprises a BKCa antagonist peptide.

62. The composition of matter of claim 61, wherein the BKCa antagonist peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

29, 35, and 38 through 41 as set forth in Table 18.

63. The composition of matter of claim 61, wherein at least one P comprises an IbTx peptide, a Slotoxin peptide, a BmTx1 peptide, or BuTx peptide, or a peptide analog of any of these.

64. The composition of matter of claim 63, wherein the IbTx peptide, Slotoxin peptide, BmTx1 peptide, BuTx peptide, or peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

38 and 357 through 398 as set forth in Table 19.

65. The composition of matter of claim 1, wherein at least one P comprises a Martentoxin peptide or Martentoxin peptide analog.

66. The composition of matter of claim 65, wherein the Martentoxin peptide or Martentoxin peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

35 and 399 through 408 as set forth Table 20.

67. The composition of matter of claim 1, wherein at least one P comprises a N-type calcium channel inhibitor peptide.

68. The composition of matter of claim 67, wherein the N-type calcium channel inhibitor peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

64 through 66, 347, 409, 1364 through 1367 as set forth in Table 21.

69. The composition of matter of claim 1, wherein at least one P comprises an ω

MVIIA peptide or ω

MVIIA peptide analog.

70. The composition of matter of claim 69, wherein the ω

MVIIA peptide or ω

MVIIA peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS;

65 and 410 through 421 as set forth in Table 22.

71. The composition of matter of claim 1, wherein at least one P comprises a GVIA peptide or GVIA peptide analog.

72. The composition of matter of claim 71, wherein the GVIA peptide or GVIA peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

64 and 422 through 429 as set forth in Table 23.

73. The composition of matter of claim 1, wherein at least one P comprises a Ptu1 peptide or Ptu1 peptide analog.

74. The composition of matter of claim 73, wherein the Ptu1 peptide or Ptu1 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

66 and 430 through 437 as set forth in Table 24.

75. The composition of matter of claim 1, wherein at least one P comprises a T-type calcium channel, P2X, or TRP inhibitor peptide.

76. The composition of matter of claim 1, wherein at least one P comprises a ProTx1 peptide or ProTx1 peptide analog.

77. The composition of matter of claim 76, wherein the ProTx1 is a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:

56, and 438 through 445 as set forth in Table 25.

78. The composition of matter of claim 1, wherein at least one P comprises a BeKM1 peptide or BeKM1 peptide anaolg.

79. The composition of matter of claim 78, wherein the BeKM1 peptide or BeKM1 peptide analog comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

63, and 446 through 458 as set forth in Table 26.

80. The composition of matter of claim 1, wherein at least one P comprises a sodium channel inhibitor peptide.

81. The composition of matter of claim 80, wherein the sodium channel inhibitor peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

459 through 469 as set forth in Table 27.

82. The composition of matter of claim 1, wherein at least one P comprises a chloride channel inhibitor peptide.

83. The composition of matter of claim 82, wherein the chloride channel inhibitor peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

67 and 470 through 493 as set forth in Table 28.

84. The composition of matter of claim 1, wherein at least one P comprises a Kv2.1 inhibitor peptide.

85. The composition of matter of claim 84, wherein the Kv2.1 inhibitor peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

494 through 506 as set forth in Table 29.

86. The composition of matter of claim 1 wherein at least one P comprises a inhibitor peptide of Kv4.3 and Kv4.2.

87. The composition of matter of claim 86, wherein the inhibitor peptide of Kv4.3 and Kv4.2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

57 and 507 through 518 as set forth in Table 30.

88. The composition of matter of claim 1, wherein at least one P comprises a nACHR channel inhibitor peptide.

89. The composition of matter of claim 88, wherein the nACHR channel inhibitor peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

519 through 541 as set forth in Table 31.

90. The composition of matter of claim 1, wherein at least one P comprises an Agatoxin peptide or Agatoxin peptide analog.

91. The composition of matter of claim 1, wherein at least one P comprises comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

959 through 975, 1275 through 1287, and 1368 as set forth in Table 32.

92. A DNA encoding a composition of matter of claim 1.

93. An expression vector comprising the DNA of claim 92.

94. A host cell comprising the expression vector of claim 93.

95. The host cell of claim 94, wherein the cell is a eukaryotic cell.

96. The host cell of claim 94, wherein the cell is a mammalian cell.

97. The host cell of claim 94, wherein the cell is a CHO cell.

98. The host cell of claim 94, wherein the cell is a prokaryotic cell.

99. The host cell of claim 94, wherein the cell is an E. coli cell.

100. The composition of matter of claim 1, further comprising an additional pharmacologically active, covalently bound peptide.

101. The composition of matter of claim 100, wherein the additional peptide is bound to F¹ or F².

102. The composition of matter of claim 100, wherein the additional peptide is bound to P.

103. The composition of matter claim 1, further comprising an agonistic peptide or an antagonistic peptide, in relation to the activity of the toxin peptide, or a targeting peptide.

127. A pharmaceutical composition, comprising the composition of any of claims 1, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, or 126 and a pharmaceutically acceptable carrier.

128. A method of preventing or mitigating a relapse of a symptom of multiple sclerosis, comprising administering to a patient, who has previously experienced at least one symptom of multiple sclerosis, a prophylactically effective amount of the composition of matter of any of claims 1, 38, 39, 48, 49, 50, 51, 52, 53, 54, 104, 109, 114, or 115, such that the at least one symptom of multiple sclerosis is prevented from recurring or is mitigated.

129. The method of claim 128, wherein the composition of matter comprises a Kv1.3 antagonist peptide.

130. The method of claim 128, wherein the composition of matter comprises a ShK peptide, an OSK1 peptide, a ChTx peptide, or a Maurotoxin peptide, or a peptide analog of any of these.

131. A method of treating an autoimmune disorder, comprising administering to a patient who has been diagnosed with an autoimmune disorder selected from the the group consisting of multiple sclerosis, type 1 diabetes, psoriasis, inflammatory bowel disease, contact-mediated dermatitis, rheumatoid arthritis, psoriatic arthritis, asthma, allergy, restinosis, systemic sclerosis, fibrosis, scleroderma, glomerulonephritis, Sjogren syndrome, inflammatory bone resorption, transplant rejection, graft-versus-host disease, and lupus, a therapeutically effective amount of the composition of matter of any of claims 1, 38, 39, 48, 49, 50, 51, 52, 53, 54, 104, 109, 114, or 115 whereby at least one symptom of the disorder is alleviated in the patient.

132. The method of claim 131, wherein the composition of matter comprises a Kv1.3 antagonist peptide or IKCa1 antagonist peptide.

133. The method of claim 131, wherein the composition of matter comprises a ShK peptide, an OSK1 peptide, a ChTx peptide, or a Maurotoxin peptide, or a peptide analog of any of these.

134. The composition of matter of claim 1, wherein any f or any g is 1, and L is a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:

79, 84, and 637 through 656.

104. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

88, 89, 92, 148 through 200, 548 through 561, 884 through 949, and 1295 through 1300 as set forth in Table 2.

105. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

201 through 225 as set forth in Table 3.

106. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

242 through 248 and 250 through 260 as set forth in Table 4.

107. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

261 through 275 as set forth in Table 5.

108. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

276 through 293 as set forth in Table 6.

109. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

980 through 1274, 1303, and 1308 as set forth in Table 7.

110. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

299 through 315 as set forth in Table 8.

111. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

316 through 318 as set forth in Table 9.

112. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence SEQ ID NO:

319 as set forth in Table 10.

113. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

327 and 328 as set forth in Table 11.

114. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

330 through 337, 341, 1301, 1302, 1304 through 1307, 1309, 1311, 1312, and 1315 through 1336 as set forth in Table 13.

115. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

1369 through 1390 as set forth in Table 14.

116. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

348 through 353 as set forth in Table 16.

117. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

357 through 362, 364 through 368, 370, 372 through 385, and 387 through 398 as set forth in Table 19.

118. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

399 through 408 as set forth in Table 20.

119. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

410 through 421 as set forth in Table 22.

120. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

422, 424, 426, and 428 as set forth in Table 23.

121. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

430 through 437 as set forth in Table 24.

122. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

438 through 445 as set forth in Table 25.

123. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

447, 449, 451, 453, 455, and 457 as set forth in Table 26.

124. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

470 through 482 and 484 through 493 as set forth in Table 28.

125. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

495 through 506 as set forth in Table 29.

126. A composition of matter, comprising a toxin peptide analog that comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:

507 through 518 as set forth in Table 30.