Peptides for the treatment of hearing

• US 8,580,748 B2
• Filed: 04/05/2012
• Issued: 11/12/2013
• Est. Priority Date: 04/06/2011
• Status: Active Grant

• Current Assignee: 13therapeutics, Inc.
• Original Assignee: 13therapeutics, Inc.
• Inventors: McCoy, Sharon L., Hefeneider, Steven H.
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): Lee, Jia-Hai
• Application Number:
  US13/440,591
• Publication Number:
  US 20120258921A1
• Time in Patent Office: 586 Days
• Field of Search: None
• US Class Current: 514/21.5
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/162 from virus
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Peptides for the treatment of inflammation, and therapeutic uses and methods of using the same are disclosed. Peptides including a transducing sequence are effective for inhibiting cytokine activity and TNF-α secretion through interaction with toll-like receptor signaling pathways. Experiments are described illustrating the efficacy of the compounds in treating otitis media, noise-induced hearing loss, age-related hearing loss, and improvement of ordinary hearing.

Claims

1. A method of treating noise-induced hearing loss, the method comprising administering to a subject in need or want of relief thereof a therapeutically-effective amount of a peptide that is:

a peptide of Formula (I) or Formula (II),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (I),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (II), wherein

each cap^N is independently H, alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group, or both cap^N groups together with N form a heterocycle;

tran^N and tran^C are each independently a transducing sequence or absent;

pep^N and pep^C are each independently an amino acid sequence or absent;

X¹ is A, K, an acidic amino acid residue, or is absent;

X² is A, I, L, or V;

X³ is A, D, I, L, P, or V;

X⁴ is A, E, I, Y, or a basic amino acid residue;

X⁵ is A, I, L, or V;

X⁶ is A, G, S, T, or Y;

X⁷ is A, E, I, L, or V;

X⁸ is A, P, S, T, or an aromatic amino acid residue;

X⁹ is A, K, or an acidic amino acid residue;

X¹⁰ is A, C, M, S, α

-aminobutyric acid, or norvaline;

X¹¹ is A, I, L, V, or is absent;

X¹² is G or is absent;

x is 1, 2, or 3;

cap^C is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and

each amino acid residue side chain is independently uncapped or capped with a capping group, or a stereoisomer or pharmaceutically-acceptable salt of any of the foregoing peptides, wherein the amino acid sequence of the peptide is not SEQ ID NO;

183, SEQ ID NO;

184, SEQ ID NO;

185, SEQ ID NO;

186, SEQ ID NO;

369, or SEQ ID NO;

378.

2. The method of claim 1, wherein at least one amino acid residue of the peptide possesses the D-configuration.

3. The method of claim 1, wherein the transducing sequence is a poly-arginine sequence.

4. The method of claim 3, wherein the poly-arginine sequence consists of about nine arginine residues.

5. The method of claim 3, wherein at least one arginine residue of the poly-arginine sequence possesses the D-configuration.

6. The method of claim 3, wherein each residue of the poly-arginine sequence possesses the D-configuration.

7. The method of claim 1, wherein the peptide is a peptide of Formula (I).

8. The method of claim 7, wherein X¹ is A, D, E, K or is absent;

X⁴ is A, E, H, I, K, R, or Y;

X⁸ is A, F, P, S, T, W, or Y; and

X⁹ is A, D, E, or K.

9. The method of claim 7, wherein cap^N is H and cap^C is OH.

10. The method of claim 7, wherein at least one of amino acid residues X^1-11 possesses the D-configuration.

11. The method of claim 7, wherein pep^N, pep^C, and tran^N are absent, and tran^C is the transducing sequence.

12. The method of claim 1, wherein the peptide is a peptide of any one of SEQ ID NOS:

131-182, 317-361, and 363-368.

13. The method of claim 1, wherein the peptide is administered orally, topically, intraaurally, parenterally, intravenously, intra-arterially, subcutaneously, intramuscularly, intracranially, or intranasally.

14. The method of claim 1, wherein the peptide is administered topically.

15. The method of claim 1, wherein the peptide is administered to the skin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingual cavity.

16. The method of claim 1, wherein the peptide is administered to the tympanic membrane.

17. The method of claim 1, wherein the peptide is administered in the form of a drop.

18. The method of claim 1, wherein the subject is a human.

19. The method of claim 1, wherein the peptide is SEQ ID NO 133.

20. The method of claim 1, wherein the peptide is SEQ ID NO 141.

21. The method of claim 1, wherein the peptide is SEQ ID NO 151.

22. The method of claim 1, wherein the peptide is SEQ ID NO 166.

23. The method of claim 1, wherein the peptide is SEQ ID NO 167.

24. The method of claim 1, wherein the peptide is SEQ ID NO 181.

25. The method of claim 1, wherein the peptide is SEQ ID NO 182.

26. The method of claim 1, wherein the peptide is SEQ ID NO 319.

27. The method of claim 1, wherein the peptide is SEQ ID NO 327.

28. The method of claim 1, wherein the peptide is SEQ ID NO 337.

29. The method of claim 1, wherein the peptide is SEQ ID NO 352.

30. The method of claim 1, wherein the peptide is SEQ ID NO 353.

31. The method of claim 1, wherein the peptide is SEQ ID NO 367.

32. The method of claim 1, wherein the peptide is SEQ ID NO 368.

97. The method of claim 1, wherein the peptide is administered in the form of an ointment, cream, liquid, gel, or salve.

98. The method of claim 1, wherein the peptide is administered in the form of an aerosol, vapor, spray, or mist.

33. A method of treating age-related hearing loss, the method comprising administering to a subject in need or want of relief thereof a therapeutically-effective amount of a peptide that is:

a peptide of Formula (I) or Formula (II),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (I),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (II), wherein

each cap^N is independently H, alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group, or both cap^N groups together with N form a heterocycle;

tran^N and tran^C are each independently a transducing sequence or absent;

pep^N and pep^C are each independently an amino acid sequence or absent;

X¹ is A, K, an acidic amino acid residue, or is absent;

X² is A, I, L, or V;

X³ is A, D, I, L, P, or V;

X⁴ is A, E, I, Y, or a basic amino acid residue;

X⁵ is A, I, L, or V;

X⁶ is A, G, S, T, or Y;

X⁷ is A, E, I, L, or V;

X⁸ is A, P, S, T, or an aromatic amino acid residue;

X⁹ is A, K, or an acidic amino acid residue;

X¹⁰ is A, C, M, S, α

-aminobutyric acid, or norvaline;

X¹¹ is A, I, L, V, or is absent;

X¹² is G or is absent;

x is 1, 2, or 3;

cap^C is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and

each amino acid residue side chain is independently uncapped or capped with a capping group,

or a stereoisomer or pharmaceutically-acceptable salt of any of the foregoing peptides, wherein the amino acid sequence of the peptide is not SEQ ID NO;

183, SEQ ID NO;

184, SEQ ID NO;

185, SEQ ID NO;

186, SEQ ID NO;

369, or SEQ ID NO;

378.

34. The method of claim 33, wherein at least one amino acid residue of the peptide possesses the D-configuration.

35. The method of claim 33, wherein the transducing sequence is a poly-arginine sequence.

36. The method of claim 33, wherein the poly-arginine sequence consists of about nine arginine residues.

37. The method of claim 33, wherein at least one arginine residue of the poly-arginine sequence possesses the D-configuration.

38. The method of claim 33, wherein each residue of the poly-arginine sequence possesses the D-configuration.

39. The method of claim 33, wherein the peptide is a peptide of Formula (I).

40. The method of claim 39, wherein X¹ is A, D, E, K or is absent;

X⁴ is A, E, H, I, K, R, or Y;

X⁸ is A, F, P, S, T, W, or Y; and

X⁹ is A, D, E, or K.

41. The method of claim 39, wherein cap^N is H and cap^C is OH.

42. The method of claim 39, wherein at least one of amino acid residues X^1-11 possesses the D-configuration.

43. The method of claim 39, wherein pep^N, pep^C, and tran^N are absent, and tran^C is the transducing sequence.

44. The method of claim 33, wherein the peptide is a peptide of any one of SEQ ID NOS:

131-182, 317-361, and 363-368.

45. The method of claim 33, wherein the peptide is administered orally, topically, intraaurally, parenterally, intravenously, intra-arterially, subcutaneously, intramuscularly, intracranially, or intranasally.

46. The method of claim 33, wherein the peptide is administered topically.

47. The method of claim 33, wherein the peptide is administered to the skin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingual cavity.

48. The method of claim 33, wherein the peptide is administered to the tympanic membrane.

49. The method of claim 33, wherein the peptide is administered in the form of a drop.

50. The method of claim 33, wherein the subject is a human.

51. The method of claim 33, wherein the peptide is SEQ ID NO 133.

52. The method of claim 33, wherein the peptide is SEQ ID NO 141.

53. The method of claim 33, wherein the peptide is SEQ ID NO 151.

54. The method of claim 33, wherein the peptide is SEQ ID NO 166.

55. The method of claim 33, wherein the peptide is SEQ ID NO 167.

56. The method of claim 33, wherein the peptide is SEQ ID NO 181.

57. The method of claim 33, wherein the peptide is SEQ ID NO 182.

58. The method of claim 33, wherein the peptide is SEQ ID NO 319.

59. The method of claim 33, wherein the peptide is SEQ ID NO 327.

60. The method of claim 33, wherein the peptide is SEQ ID NO 337.

61. The method of claim 33, wherein the peptide is SEQ ID NO 352.

62. The method of claim 33, wherein the peptide is SEQ ID NO 353.

63. The method of claim 33, wherein the peptide is SEQ ID NO 367.

64. The method of claim 33, wherein the peptide is SEQ ID NO 368.

99. The method of claim 33, wherein the peptide administered is in the form of an ointment, cream, liquid, gel, or salve.

100. The method of claim 33, wherein the peptide administered is in the form of an aerosol, vapor, spray, or mist.

65. A method of improving hearing, the method comprising administering to a subject in need or want thereof a therapeutically-effective amount of a peptide that is:

a peptide of Formula (I) or Formula (II),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹-X²-X³-X⁴-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹-X¹²)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (I),

(cap^N)(cap^N)N-tran^N-pep^N-(X¹²-X¹¹-X¹⁰-X⁹-X⁸-X⁷-X⁶-X⁵-X⁴-X³-X²-X¹)_x-pep^C-tran^C-C(O)-cap^C 

 

Formula (II), wherein

each cap^N is independently H, alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group, or both cap^N groups together with N form a heterocycle;

tran^N and tran^C are each independently a transducing sequence or absent;

pep^N and pep^C are each independently an amino acid sequence or absent;

X¹ is A, K, an acidic amino acid residue, or is absent;

X² is A, I, L, or V;

X³ is A, D, I, L, P, or V;

X⁴ is A, E, I, Y, or a basic amino acid residue;

X⁵ is A, I, L, or V;

X⁶ is A, G, S, T, or Y;

X⁷ is A, E, I, L, or V;

X⁸ is A, P, S, T, or an aromatic amino acid residue;

X⁹ is A, K, or an acidic amino acid residue;

X¹⁰ is A, C, M, S, α

-aminobutyric acid, or norvaline;

X¹¹ is A, I, L, V, or is absent;

X¹² is G or is absent;

x is 1, 2, or 3;

cap^C is OH, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, or a heterocycle; and

each amino acid residue side chain is independently uncapped or capped with a capping group,

or a stereoisomer or pharmaceutically-acceptable salt of any of the foregoing peptides, wherein the amino acid sequence of the peptide is not SEQ ID NO;

183, SEQ ID NO;

184, SEQ ID NO;

185, SEQ ID NO;

186, SEQ ID NO;

369, or SEQ ID NO;

378.

66. The method of claim 65, wherein at least one amino acid residue of the peptide possesses the D-configuration.

67. The method of claim 65, wherein the transducing sequence is a poly-arginine sequence.

68. The method of claim 65, wherein the poly-arginine sequence consists of about nine arginine residues.

69. The method of claim 65, wherein at least one arginine residue of the poly-arginine sequence possesses the D-configuration.

70. The method of claim 65, wherein each residue of the poly-arginine sequence possesses the D-configuration.

71. The method of claim 65, wherein the peptide is a peptide of Formula (I).

72. The method of claim 71, wherein X¹ is A, D, E, K or is absent;

X⁴ is A, E, H, I, K, R, or Y;

X⁸ is A, F, P, S, T, W, or Y; and

X⁹ is A, D, E, or K.

73. The method of claim 71, wherein cap^N is H and cap^C is OH.

74. The method of claim 71, wherein at least one of amino acid residues X^1-11 possesses the D-configuration.

75. The method of claim 71, wherein pep^N, pep^C, and tran^N are absent, and tran^C is the transducing sequence.

76. The method of claim 65, wherein the peptide is a peptide of any one of SEQ ID NOS:

131-182, 317-361, and 363-368.

77. The method of claim 65, wherein the peptide is administered orally, topically, intraaurally, parenterally, intravenously, intra-arterially, subcutaneously, intramuscularly, intracranially, or intranasally.

78. The method of claim 65, wherein the peptide is administered topically.

79. The method of claim 65, wherein the peptide is administered to the skin, hair, outer ear, tympanic membrane, buccal cavity, nasal cavity, or sublingual cavity.

80. The method of claim 65, wherein the peptide is administered to the tympanic membrane.

81. The method of claim 65, wherein the peptide is administered in the form of a drop.

82. The method of claim 65, wherein the subject is a human.

83. The method of claim 65, wherein the peptide is SEQ ID NO 133.

84. The method of claim 65, wherein the peptide is SEQ ID NO 141.

85. The method of claim 65, wherein the peptide is SEQ ID NO 151.

86. The method of claim 65, wherein the peptide is SEQ ID NO 166.

87. The method of claim 65, wherein the peptide is SEQ ID NO 167.

88. The method of claim 65, wherein the peptide is SEQ ID NO 181.

89. The method of claim 65, wherein the peptide is SEQ ID NO 182.

90. The method of claim 65, wherein the peptide is SEQ ID NO 319.

91. The method of claim 65, wherein the peptide is SEQ ID NO 327.

92. The method of claim 65, wherein the peptide is SEQ ID NO 337.

93. The method of claim 65, wherein the peptide is SEQ ID NO 352.

94. The method of claim 65, wherein the peptide is SEQ ID NO 353.

95. The method of claim 65, wherein the peptide is SEQ ID NO 367.

96. The method of claim 65, wherein the peptide is SEQ ID NO 368.

101. The method of claim 65, wherein the peptide administered is in the form of an ointment, cream, liquid, gel, or salve.

102. The method of claim 65, wherein the peptide administered is in the form of an aerosol, vapor, spray, or mist.