GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS
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Abstract
Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming lactam bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, substitution of carboxy terminal amino acids, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (K-RNRNNIA) and SEQ ID NO: 28 (KRNR).
188 Citations
100 Claims
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1-65. -65. (canceled)
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66. A non-native glucagon peptide comprising the sequence of SEQ ID NO:
- 55 or an analog of SEQ ID NO;
55, wherein said analog is not a naturally occurring peptide and said analog differs from SEQ ID NO;
55 by 1 to 3 amino acid modifications, selected from positions 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, 24, 27, 28, and 29, wherein said glucagon peptide comprises an intramolecular bridge between the side chains of the amino acids at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28, and wherein the glucagon peptide exhibits enhanced activity at the GLP-1 receptor as compared to native glucagon. - View Dependent Claims (67, 68, 69, 70, 71, 72, 73, 76, 78, 80, 82, 84, 92, 95, 98)
- 55 or an analog of SEQ ID NO;
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74. A non-native glucagon peptide comprising the sequence of SEQ ID NO:
- 55 or an analog of SEQ ID NO;
55, wherein said analog is not a naturally occurring peptide and said analog differs from SEQ ID NO;
55 by 1 to 3 amino acid modifications, selected from positions 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, 24, 27, 28, and 29, wherein the amino acid at position 16 is glutamic acid, the amino acid at position 20 is lysine, and the C-terminal carboxylic acid group is replaced with an amide, and wherein the glucagon peptide exhibits enhanced activity at the GLP-1 receptor as compared to native glucagon. - View Dependent Claims (75, 77, 79, 81, 83, 93, 96, 99)
- 55 or an analog of SEQ ID NO;
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85. An analog of the glucagon amino acid sequence of SEQ ID NO:
- 1 that comprises an intramolecular bridge between the side chains of the amino acids at positions 12 and 16, 16 and 20, 20 and 24, or 24 and 28, wherein the analog exhibits enhanced activity at the GLP-1 receptor as compared to native glucagon.
- View Dependent Claims (86, 87, 88, 89, 90, 94, 97, 100)
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91. A glucagon peptide comprising an amino acid sequence selected from the group consisting of:
- SEQ ID NO;
70 through SEQ ID NO;
514.
- SEQ ID NO;
Specification