GLUCAGON ANALOGS EXHIBITING ENHANCED SOLUBILITY AND STABILITY IN PHYSIOLOGICAL pH BUFFERS
First Claim
Patent Images
1. A glucagon peptide with glucagon agonist activity, comprising (i) the amino acid sequence of SEQ ID NO:
- 1 with one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 substituted with an α
,α
-disubstituted amino acid, and (ii) a C-terminal alpha carboxylate.
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Abstract
Modified glucagon peptides are disclosed having improved solubility and/or half-life while retaining glucagon agonist activity. The glycogen peptides have been modified by substitution of native amino acids with, and/or addition of, charged amino acids to the carboxy terminus of the peptide. The modified glucagon agonists can be further modified by pegylation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, or both to further enhance the solubility of the glucagon agonist analogs.
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Citations
98 Claims
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1. A glucagon peptide with glucagon agonist activity, comprising (i) the amino acid sequence of SEQ ID NO:
- 1 with one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 substituted with an α
,α
-disubstituted amino acid, and (ii) a C-terminal alpha carboxylate.
- 1 with one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 substituted with an α
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2-24. -24. (canceled)
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25. A glucagon peptide with glucagon agonist activity, comprising the amino acid sequence of SEQ ID NO:
- 77, wherein the Xaa at position 3 is an amino acid comprising a side chain of Structure I, II, or III;
- View Dependent Claims (26, 30, 32, 33, 34, 35, 36, 82, 87, 89, 90, 94, 95, 97, 98)
- 77, wherein the Xaa at position 3 is an amino acid comprising a side chain of Structure I, II, or III;
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27-29. -29. (canceled)
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31. (canceled)
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37-42. -42. (canceled)
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43. A glucagon peptide with glucagon agonist activity, comprising the amino acid sequence:
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X1-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Z (SEQ ID NO;
39) with 1 to 3 amino acid modifications thereto,wherein X1 and/or X2 is a non-native amino acid that reduces susceptibility of the glucagon peptide to cleavage by dipeptidyl peptidase IV (DPP-IV), wherein Z is selected from the group consisting of —
COOH, -Asn-COOH, Asn-Thr-COOH, and Y—
COOH, wherein Y is 1 to 2 amino acids, andwherein a lactam bridge connects the side chains of an amino acid at position i and an amino acid at position i+4, wherein i is 12, 16, 20 or 24.
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44-57. -57. (canceled)
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58. A glucagon peptide with glucagon agonist activity, comprising the amino acid sequence:
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59-73. -73. (canceled)
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74. An analog of the glucagon peptide of SEQ ID NO:
- 1 with up to 10 modifications relative to native glucagon (SEQ ID NO;
1) that has glucagon agonist activity and comprises(a) at least one amino acid modification selected from the group consisting of; substitution of Asn at position 28 with a charged amino acid; (ii) substitution of Asn at position 28 with a charged amino acid selected from the group consisting of Lys, Arg, His, Asp, Glu, cysteic acid, and homocysteic acid; (iii) substitution at position 28 with Asn, Asp, or Glu; (iv) substitution at position 28 with Asp; (v) substitution at position 28 with Glu; (vi) substitution of Thr at position 29 with a charged amino acid; (vii) substitution of Thr at position 29 with a charged amino acid selected from the group consisting of Lys, Arg, His, Asp, Glu, cysteic acid, and homocysteic acid; (viii) substitution at position 29 with Asp, Glu, or Lys; (ix) substitution at position 29 with Glu; (x) insertion of 1-3 charged amino acids after position 29; (xi) insertion after position 29 of Glu or Lys; (xii) insertion after position 29 of Gly-Lys or Lys-Lys;
or a combination thereof;(b) and at least one amino acid modification selected from Group A or Group B, or a combination thereof; wherein Group A is an amino acid modification selected from the group consisting of substitution of Asp at position 15 with Glu, and substitution of Ser at position 16 with Thr or AIB; and wherein Group B is an amino acid modification selected from the group consisting of; (i) substitution of His at position 1 with a non-native amino acid that reduces susceptibility of the glucagon peptide to cleavage by dipeptidyl peptidase IV (DPP-IV), (ii) substitution of Ser at position 2 with a non-native amino acid that reduces susceptibility of the glucagon peptide to cleavage by dipeptidyl peptidase IV (DPP-IV), (iii) substitution of Tyr at position 10 with Phe or Val; (iv) substitution of Lys at position 12 with Arg; (v) substitution of Gln at position 20 with Ala or AIB; (vi) substitution of Asp at position 21 with Glu; (vii) substitution of Gln at position 24 with Ala or AIB; (viii) substitution of Met at position 27 with Leu or Nle; (ix) deletion of amino acids at positions 27-29; (x) deletion of amino acids at positions 28-29; (xi) deletion of the amino acid at positions 29; (xii) or a combination thereof. - View Dependent Claims (75, 78)
- 1 with up to 10 modifications relative to native glucagon (SEQ ID NO;
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76. (canceled)
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77. (canceled)
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79. (canceled)
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80. A glucagon peptide comprising the amino acid sequence of any of SEQ ID NOs:
- 40-56.
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81. (canceled)
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83-86. -86. (canceled)
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88. (canceled)
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91-93. -93. (canceled)
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96. (canceled)
Specification