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1. WO2020142102 - CONOTOXIN PEPTIDE ANALOGS AND USES FOR THE TREATMENT OF PAIN AND INFLAMMATORY CONDITIONS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is claimed is:

1. A conotoxin peptide analog of Formula (I) (SEQ ID NO:93):


or a pharmaceutically acceptable salt thereof,

wherein

X is X 1 1

AA or X 1

AA X 2

AA ; wherein XAA is Tyr, Phe, Trp, or a D-isomer of Tyr, Phe, or Trp, and X 2

AA is N-Me-Gly, D-Tyr, or N-Me-Tyr;

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group.

2. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the triazole bridge is

, wherein the single wavy line ( ) indicates the point of attachment of the triazole bridge to the C1 carbon of the conotoxin peptide analog, and the double wavy lines ( ) indicate the point of attachment of the triazole bridge to the C2 carbon of the conotoxin peptide analog; and wherein x is 1, 2, 3, or 4; and y is 2, 3 or 4.

3. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 2, wherein the


4. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 2, wherein the

triazole bridge i

5. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 2-4, wherein x is 1, 2, or 3.

6. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 5, wherein x is 1.

7. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 2-6, wherein y is 2 or 3.

8. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 7, wherein y is 3.

9. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 2, wherein x is 1, 2, or 3, and y is 2 or 3.

10. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 3, wherein x is 1 and y is 3.

11. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 3, wherein x is 2 and y is 3.

12. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 3, wherein x is 2 and y is 2.

13. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 4, wherein x is 2 and y is 2.

14. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 4, wherein x is 1 and y is 3.

15. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 10, wherein


, wherein the single wavy line ( ) indicates the point of attachment of the triazole bridge to the C1 carbon of the conotoxin peptide analog, and the double wavy lines (
) indicate the point of attachment of the triazole bridge to the C2 carbon of the conotoxin peptide analog.

16. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-15, wherein X is X 1

AA .

17. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-15, wherein X is X 1

AA X 2

AA .

18. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 16 or 17, wherein X 1

AA is selected from the group consisting of Tyr, D-Tyr and Phe.

19. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-16, wherein X is Tyr.

20. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-19, wherein the C-terminus of the conotoxin peptide analog is OH.

21. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-19, wherein the C-terminus of the conotoxin peptide analog is NH2.

22. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ia) (SEQ ID NO:94):

23. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 22, wherein R1 is OH.

24. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 22, wherein R1 is NH2.

25. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ig) (SEQ ID NO:30):

26. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ih) (SEQ ID NO:33):

27. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ii) (SEQ ID NO:36):

28. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ik) (SEQ ID NO:42):

29. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Il) (SEQ ID NO:45):

30. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Im) (SEQ ID NO:48):

31. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (In) (SEQ ID NO:51):

32. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Io) (SEQ ID NO:54):

33. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 1, wherein the conotoxin peptide analog is of Formula (Ip) (SEQ ID NO:57):

34. A PEGylated conotoxin peptide analog or pharmaceutically acceptable salt thereof, wherein the conotoxin peptide analog is of Formula (I) (SEQ ID NO:93):

wherein

X is X 1

AA or X 1

AA X 2

AA ; wherein X 1

AA is Tyr, Phe, Trp, or a D-isomer of Tyr, Phe, or Trp, and X 2

AA is N-Me-Gly, D-Tyr, or N-Me-Tyr;

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group; and

wherein the conotoxin peptide analog is covalently attached directly or via a linking group to one or more polyethylene glycol (PEG) polymers.

35. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the triazole bridge is


, wherein the single wavy line ( ) indicates the point of attachment of the triazole bridge to the C1 carbon of the conotoxin peptide analog, and the double wavy lines ( ) indicate the point of attachment of the triazole bridge to the C2 carbon of the conotoxin peptide analog; and wherein x is 1, 2, 3, or 4; and y is 2, 3 or 4.

36. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 35,

37. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 35,

38. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 35-37, wherein x is 1, 2, or 3.

39. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 38, wherein x is 1.

40. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 35-39, wherein y is 2 or 3.

41. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 40, wherein y is 3.

42. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 35, wherein x is 1, 2, or 3, and y is 2 or 3.

43. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 36, wherein x is 1 and y is 3.

44. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 36, wherein x is 2 and y is 3.

45. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 36, wherein x is 2 and y is 2.

46. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 37, wherein x is 2 and y is 2.

47. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 37, wherein x is 1 and y is 3.

48. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 43,


, wherein the single wavy line ( ) indicates the point of attachment of the triazole bridge to the C1 carbon of the conotoxin peptide analog, and the double wavy lines ( ) indicate the point of attachment of the triazole bridge to the C2 carbon of the conotoxin peptide analog.

49. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-48, wherein X is X 1

AA .

50. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-48, wherein X is X 1

AA X 2

AA .

51. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 49 or 50, wherein X 1

AA is selected from the group consisting of Tyr, D-Tyr and Phe.

52. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-49, wherein X is Tyr.

53. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-52, wherein the C-terminus of the conotoxin peptide analog is OH.

54. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-52, wherein the C-terminus of the conotoxin peptide analog is NH2.

55. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ia) (SEQ ID NO:94)

wherein R1 is OH or NH2.

56. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 55, wherein R1 is OH.

57. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 55, wherein R1 is NH2.

58. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ig) (SEQ ID NO:30):

59. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ih) (SEQ ID NO:33):

60. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ii) (SEQ ID NO:36):

61. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ik) (SEQ ID NO:42):


62. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (II) (SEQ ID NO:45):


63. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Im) (SEQ ID NO:48):

64. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (In) (SEQ ID NO:51):

65. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Io) (SEQ ID NO:54):

66. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the conotoxin peptide analog is of Formula (Ip) (SEQ ID NO:57):

67. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-66, wherein the conotoxin peptide analog is covalently attached to one PEG polymer.

68. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 67, wherein the PEG polymer is covalently attached to the N-terminus of the conotoxin peptide analog.

69. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 67, wherein the PEG polymer is covalently attached to the C-terminus of the conotoxin peptide analog.

70. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 67, wherein the PEG polymer is covalently attached to an amino acid residue position that is not the N-terminus or the C-terminus of the conotoxin peptide analog.

71. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 67-70, wherein the PEG polymer is covalently attached to the conotoxin peptide analog via a linking group.

72. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 71,

wherein the linking group is a valerate linker having a formula
.

73. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 71, wherein the linking group is a butylene.

74. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 71, wherein the linking group is a carbonyl.

75. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 67-74, wherein the PEG polymer is a linear or branched PEG polymer.

76. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 75, wherein the PEG polymer is a linear PEG polymer.

77. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 76, wherein the PEG polymer has molecular weight in the range of 10 kDa and 40 kDa.

78. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 77, wherein the PEG polymer is a linear 30 kDa PEG polymer.

79. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 78, wherein the PEG polymer is a linear 30 kDa mPEG polymer.

80. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIa) (SEQ ID NO:83):

81. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIg) (SEQ ID NO:95):

l


82. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIh) (SEQ ID NO:96):

83. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34,

84. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34,

85. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIl) (SEQ ID NO:99):

86. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIm) (SEQ ID NO:100):

87. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIn) (SEQ ID NO:101):

88. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIo) (SEQ ID NO:102):

89. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 34, wherein the PEGylated conotoxin peptide analog is of Formula (IIp) (SEQ ID NO:103):

90. A conotoxin peptide analog of Formula (Ib) (SEQ ID NO:104):

or a pharmaceutically acceptable salt thereof,

wherein R2 is OH or NH2.

91. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 90, wherein R2 is OH.

92. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 90, wherein R2 is NH2.

93. A PEGylated conotoxin peptide analog or a pharmaceutically acceptable salt thereof, wherein the conotoxin peptide analog is of Formula (Ib) (SEQ ID NO:104):

wherein R2 is OH or NH2; and

wherein the conotoxin peptide analog is covalently attached directly or via a linking group to one or more polyethylene glycol (PEG) polymers.

94. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 93, wherein R2 is OH.

95. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 93, wherein R2 is NH2.

96. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 93-95, wherein the conotoxin peptide analog is covalently attached to one PEG polymer.

97. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 96, wherein the PEG polymer is attached to the N-terminus of the conotoxin peptide analog.

98. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 96, wherein the PEG polymer is attached to the C-terminus of the conotoxin peptide analog.

99. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 96, wherein the PEG is attached to an amino acid residue position that is not the N-terminus or the C-terminus of the conotoxin peptide analog.

100. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 96-99, wherein the PEG polymer is covalently attached to the conotoxin peptide analog via a linking group.

101. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim

100, wherein the linking group is a valerate linker having a formula
.

102. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 100, wherein the linking group is a butylene.

103. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 100, wherein the linking group is a carbonyl.

104. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 96-103, wherein the PEG polymer is a linear or branched PEG polymer.

105. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 104, wherein the PEG polymer is a linear PEG polymer.

106. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 105, wherein the PEG polymer has molecular weight in the range of 10 kDa and 40 kDa.

107. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 106, wherein the PEG polymer is a linear 30 kDa PEG polymer.

108. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 107, wherein the PEG polymer is a linear 30 kDa mPEG polymer.

109. The PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of claim 93, wherein the PEGylated conotoxin peptide analog is of Formula (IIb) (SEQ ID NO:105):

110. A conotoxin peptide analog selected from the group consisting of conotoxin peptide analogs Ia, Ia’, Ib, Ib’, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Ir, Is, It, Iu, and Iv, or a pharmaceutically acceptable salt thereof.

111. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 110, wherein the conotoxin peptide analog is selected from the group consisting of conotoxin peptide analogs Ia, Ia’, Ib, Ib’, Ig, Ih, Ii, Ik, Il, Im, In, Io, and Ip.

112. The conotoxin peptide analog or pharmaceutically acceptable salt of claim 110, wherein the conotoxin peptide analog is selected from the group consisting of conotoxin peptide analogs Ia, Ia’, Ib, and Ib’.

113. A pharmaceutical composition comprising the conotoxin peptide analog or

pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, and optionally a pharmaceutically acceptable carrier.

114. A method of treating or preventing a condition conducive to treatment or prevention by inhibition of an a9-containing nicotinic acetylcholine receptor (nAChR) in a subject comprising administering to the subject a therapeutically effective amount of the conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, or the pharmaceutical composition of claim 113.

115. A method of treating or preventing a condition associated with activation of an a9-containing nicotinic acetylcholine receptor (nAChR) in a subject comprising administering to the subject a therapeutically effective amount of the conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, or the pharmaceutical composition of claim 113.

116. The method of claim 114, wherein the condition conducive to treatment or prevention by inhibition of the a9-containing nAChR is pain or inflammation.

117. The method of claim 116, wherein the condition is pain.

118. The method of claim 117, wherein the pain is selected from the group consisting of general pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, somatic pain, pain induced by peripheral nerve damage, pain induced by an inflammatory disorder, pain induced by a metabolic disorder, pain induced by cancer, pain induced by chemotherapy, pain induced by a surgical procedure, and pain induced by a burn.

119. The method of claim 117, wherein the pain is cancer-related chronic pain.

120. The method of claim 114, wherein the condition conducive to treatment or prevention by inhibition of the a9-containing nAChR is an inflammatory condition.

121. The method of claim 120, wherein the inflammatory condition is selected from the group consisting of inflammation, chronic inflammation, a rheumatic disease, sepsis, fibromyalgia, inflammatory bowel disease, sarcoidosis, endometriosis, uterine fibroids, an inflammatory skin disease, an inflammatory condition of the lungs, a disease associated with inflammation of the nervous system, periodontal disease, and cardiovascular disease.

122. The method of claim 120, wherein the inflammatory condition is mediated by immune cells.

123. The method of claim 120, wherein the inflammatory condition is long-term inflammation and/or peripheral neuropathy following injury.

124. The method of claim 114, wherein the condition conducive to treatment or prevention by inhibition of the a9-containing nAChR is pain and inflammation.

125. The method of claim 116, wherein the condition conducive to treatment or prevention by inhibition of the a9-containing nAChR is inflammation and neuropathy.

126. The method of any one of claim 114-125, wherein the condition conducive to treatment or prevention by inhibition of an a9-containing nicotinic acetylcholine receptor (nAChR) is a condition conducive to treatment or prevention by inhibition of the a9a10 subtype of nAChR.

127. The method of any one of claims 114-126, wherein the subject is a human.

128. A method of treating or preventing pain or inflammation in a subject comprising administering to the subject a therapeutically effective amount of the conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, or the pharmaceutical composition of claim 113.

129. The conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, or the pharmaceutical composition of claim 113, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of an a9-containing nicotinic acetylcholine receptor (nAChR) in a subject, preferably the a9a10 subtype of nAChR, or for use in treating or preventing pain or inflammation.

130. A pharmaceutical composition comprising the conotoxin peptide analog or

pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, for use in treating or preventing a condition conducive to treatment or prevention by inhibition of an a9-containing nicotinic acetylcholine receptor (nAChR) in a subject, preferably the a9a10 subtype of nAChR, or for use in treating or preventing pain or inflammation.

131. Use of the conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 1-33, 90-92 and 110-112, or the PEGylated conotoxin peptide analog or pharmaceutically acceptable salt of any one of claims 34-89 and 93-109, or the pharmaceutical composition of claim 113, in the preparation of a medicament for treating or preventing a condition conducive to treatment or prevention by inhibition of an a9-containing nicotinic acetylcholine receptor (nAChR) in a subject, preferably the a9a10 subtype of nAChR, or for treating or preventing pain or inflammation.

132. A conotoxin peptide analog or a salt thereof, wherein the amino acid sequence of the conotoxin peptide analog is

Gly-Cys-X 3 2

AA -Thr-Asp-Pro-Arg-Cys-X 9

AA -Trp-Gln-X 1

AA -X (SEQ ID NO:106),

wherein

X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-azidoalanine, (S)-homopropargyl glycine, (S)-azidohomoalanine, (S)-azidonorvaline and (S)-bishomopropargyl glycine;

X 9

AA is Citrulline;

X 12

AA is selected from the group consisting of (S)-azidohomoalanine, (S)-homopropargyl glycine, (S)-azidonorvaline, and (S)-bishomopropargyl glycine;

wherein when X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-homopropargyl glycine, and (S)-bishomopropargyl glycine, X 12

AA is (S)-azidohomoalanine or (S)-azidonorvaline; and when X 3

AA is selected from the group consisting of (S)-azidoalanine, (S)-azidohomoalanine, and (S)-azidonorvaline, X 12

AA is (S)-homopropargyl glycine or (S)-bishomopropargyl glycine;

X is X 1 1 2

AA or XAA XAA ; wherein X 1

AA is Tyr, Phe, Trp, or a D-isomer of Tyr, Phe, or Trp, and X 2

AA is N-Me-Gly, D-Tyr, or N-Me-Tyr; and

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group.

133. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine or (S)-azidoalanine.

134. The conotoxin peptide analog or salt of claim 132, wherein X 12

AA is (S)-azidonorvaline or (S)-bishomopropargyl glycine.

135. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine and X 12

AA is (S)-azidonorvaline.

136. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-homopropargyl glycine and X 12

AA is (S)-azidonorvaline.

137. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-homopropargyl glycine and X 12

AA is (S)-azidohomoalanine.

138. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-azidohomoalanine and X 12

AA is (S)-homopropargyl glycine.

139. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-azidoalanine and X 12

AA is (S)-bishomopropargyl glycine.

140. The conotoxin peptide analog or salt of any one of claims 132-139, wherein wherein X is X 1

AA .

141. The conotoxin peptide analog or salt of any one of claims 132-139, wherein X is

X 1

AA X 2

AA .

142. The conotoxin peptide analog or salt of claim 140 or 141, wherein X 1

AA is selected from the group consisting of Tyr, D-Tyr and Phe.

143. The conotoxin peptide analog or salt of any one of claims 132-140, wherein X is Tyr.

144. The conotoxin peptide analog or salt of any one of claims 132-143, wherein the C-terminus of the conotoxin peptide analog is OH.

145. The conotoxin peptide analog or salt of any one of claims 132-143, wherein the C-terminus of the conotoxin peptide analog is NH2.

146. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is Tyr.

147. The conotoxin peptide analog or salt of claim 146, wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

148. The conotoxin peptide analog or salt of claim 146, wherein the C-terminus of the conotoxin peptide analog is an amide group.

149. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-homopropargyl glycine, X 12

AA is (S)-azidonorvaline, X is Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

150. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-homopropargyl glycine, X 12

AA is (S)-azidohomoalanine, X is Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

151. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-azidohomoalanine, X 12

AA is (S)-homopropargyl glycine, X is Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

152. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-azidoalanine, X 12

AA is (S)-bishomopropargyl glycine, X is Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

153. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is Phe; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

154. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is D-Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

155. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is Tyr-N-Me-Gly; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

156. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is Tyr-D-Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

157. The conotoxin peptide analog or salt of claim 132, wherein X 3

AA is (S)-propargyl glycine, X 12

AA is (S)-azidonorvaline, X is Tyr-N-Me-Tyr; and wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

158. A conotoxin peptide analog or a salt thereof, wherein the amino acid sequence of the conotoxin peptide analog is

Gly-Cys-X 3

AA -Thr-Asp-Pro-Arg-Cys-X 9

AA -X 10

AA -Gln-X 12

AA -Tyr (SEQ ID NO:107),

wherein

X 3

AA is (S)-propargyl glycine;

X 9

AA is Citrulline;

X 10

AA is 3-iodo-Tyr;

X 12

AA is (S)-azidonorvaline;

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group.

159. The conotoxin peptide analog or salt of claim 158, wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid group.

160. The conotoxin peptide analog or salt of claim 158, wherein the C-terminus of the conotoxin peptide analog is an amide group.

161. A method of making a conotoxin peptide analog of Formula (I) (SEQ ID NO:93) or a pharmaceutically acceptable salt thereof,

wherein

X is X 1 1 2

AA or XAA XAA ; wherein X 1

AA is Tyr, Phe, Trp, or a D-isomer of Tyr, Phe, or Trp, and X 2

AA is N-Me-Gly, D-Tyr, or N-Me-Tyr; and

wherein the C-terminus of the conotoxin peptide analog of Formula (I) is a carboxylic acid or an amide group;

comprising subjecting an intermediate conotoxin peptide analog or a salt thereof to triazole formation conditions, wherein the amino acid sequence of the intermediate conotoxin peptide analog is Gly-Cys-X 3

AA -Thr-Asp-Pro-Arg-Cys-X 9

AA -Trp-Gln-X 12

AA -X (SEQ ID NO:106), wherein

X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-azidoalanine, (S)-homopropargyl glycine, (S)-azidohomoalanine, (S)-azidonorvaline and (S)-bishomopropargyl glycine;

X 9

AA is Citrulline;

X 12

AA is selected from the group consisting of (S)-azidohomoalanine, (S)-homopropargyl glycine, (S)-azidonorvaline, and (S)-bishomopropargyl glycine;

wherein when X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-homopropargyl glycine, and (S)-bishomopropargyl glycine, X 12

AA is (S)-azidohomoalanine or (S)-azidonorvaline; when X 3

AA is selected from the group consisting of (S)-azidoalanine, (S)-azidohomoalanine, and (S)-azidonorvaline, X 12

AA is (S)-homopropargyl glycine or (S)-bishomopropargyl glycine;

X is as defined above for the conotoxin peptide analog of Formula (I); and

wherein the C-terminus of the intermediate conotoxin peptide analog is as defined above for the conotoxin peptide analog of Formula (I); and

wherein under said triazole formation conditions X 3

AA reacts with X 12

AA to form the triazole bridge in the conotoxin peptide analog of Formula (I).

162. A method of making a conotoxin peptide analog of Formula (Ib) (SEQ ID NO:104) or a pharmaceutically acceptable salt thereof,

wherein the C-terminus of the conotoxin peptide analog of Formula (Ib) is a carboxylic acid or an amide group,

comprising subjecting an intermediate conotoxin peptide analog or a salt thereof to triazole formation conditions, wherein the amino acid sequence of the intermediate conotoxin peptide analog is Gly-Cys-X 3

AA -Thr-Asp-Pro-Arg-Cys-X 9 10

AA -XAA -Gln-X 12

AA -Tyr (SEQ ID NO:107), wherein

X 3

AA is (S)-propargyl glycine;

X 9

AA is Citrulline;

X 10

AA is 3-iodo-Tyr;

X 12

AA is (S)-azidonorvaline; and

wherein the C-terminus of the intermediate conotoxin peptide analog is as defined above for the conotoxin peptide analog of Formula (Ib); and

wherein under said triazole formation conditions X 3

AA reacts with X 12

AA to form a triazole bridge

as depicted in the conotoxin peptide analog of Formula (Ib).

163. A method of making a PEGylated conotoxin peptide analog or a pharmaceutically acceptable salt thereof, comprising contacting under reaction conditions a conotoxin peptide analog or a salt thereof, with one or more reactive polyethylene glycol (PEG) polymers to form a PEGylated conotoxin peptide analog, wherein the reactive PEG polymers each comprise a reactive group covalently linked, optionally via a linking group, to a PEG polymer, and wherein each reactive group reacts under the reaction conditions to form a covalent bond with the conotoxin peptide analog whereby the conotoxin peptide analog is covalently attached directly or via a linking group to the one or more PEG polymers,

wherein the amino acid sequence of the conotoxin peptide analog is Gly-Cys-X 3

AA -Thr-Asp-Pro-Arg-Cys-X 9

AA -Trp-Gln-X 12

AA -X (SEQ ID NO:106),

wherein

X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-azidoalanine, (S)-homopropargyl glycine, (S)-azidohomoalanine, (S)-azidonorvaline and (S)-bishomopropargyl glycine;

X 9

AA is Citrulline;

X 12

AA is selected from the group consisting of (S)-azidohomoalanine, (S)-homopropargyl glycine, (S)-azidonorvaline, and (S)-bishomopropargyl glycine;

wherein when X 3

AA is selected from the group consisting of (S)-propargyl glycine, (S)-homopropargyl glycine, and (S)-bishomopropargyl glycine, X 12

AA is (S)-azidohomoalanine or (S)-azidonorvaline; when X 3

AA is selected from the group consisting of (S)-azidoalanine, (S)-azidohomoalanine, and (S)-azidonorvaline, X 12

AA is (S)-homopropargyl glycine or (S)-bishomopropargyl glycine;

X is X 1

AA or X 1 2

AA XAA ; wherein X 1

AA is Tyr, Phe, Trp, or a D-isomer of Tyr, Phe, or Trp, and X 2

AA is N-Me-Gly, D-Tyr, or N-Me-Tyr; and

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group.

164. A method of making a PEGylated conotoxin peptide analog or a pharmaceutically acceptable salt thereof, comprising contacting under reaction conditions a conotoxin peptide analog or a salt thereof, with one or more reactive polyethylene glycol (PEG) polymers to form a PEGylated conotoxin peptide analog, wherein the reactive PEG polymers each comprise a reactive group covalently linked, optionally via a linking group, to a PEG polymer, and wherein each reactive group reacts under the reaction conditions to form a covalent bond with the conotoxin peptide analog whereby the conotoxin peptide analog is covalently attached directly or via a linking group to the one or more PEG polymers,

wherein the amino acid sequence of the conotoxin peptide analog is Gly-Cys-X 3

AA -Thr-Asp-Pro-Arg-Cys-X 9 0

AA -X 1

AA -Gln-X 12

AA -Tyr (SEQ ID NO:107),

wherein

X 3

AA is (S)-propargyl glycine;

X 9

AA is Citrulline;

X 10

AA is 3-iodo-Tyr;

X 12

AA is (S)-azidonorvaline;

wherein the C-terminus of the conotoxin peptide analog is a carboxylic acid or an amide group.