COMPOUNDS EXHIBITING GLUCAGON ANTAGONIST AND GLP-1 AGONIST ACTIVITY
First Claim
Patent Images
1. A glucagon antagonist/GLP-1 agonist comprising the sequence of SEQ ID NO:
- 51, wherein the amino acids at positions 4 and 7, positions 7 and 11, positions 11 and 15, positions 15 and 19, or positions 19 and 23 of SEQ ID NO;
51 are linked via a lactam bridge, or an oxy derivative of the glucagon antagonist/GLP-1 agonist.
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Abstract
Glucagon analogs are disclosed that exhibit both glucagon antagonist and GLP-1 agonist activity. In one embodiment, the glucagon antagonist/GLP-1 agonist comprises a modified amino acid sequence of native glucagon, in which the first one to five N-terminal amino acids of native glucagon is deleted and in which the alpha helix is stabilized.
112 Citations
67 Claims
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1. A glucagon antagonist/GLP-1 agonist comprising the sequence of SEQ ID NO:
- 51, wherein the amino acids at positions 4 and 7, positions 7 and 11, positions 11 and 15, positions 15 and 19, or positions 19 and 23 of SEQ ID NO;
51 are linked via a lactam bridge, or an oxy derivative of the glucagon antagonist/GLP-1 agonist.
- 51, wherein the amino acids at positions 4 and 7, positions 7 and 11, positions 11 and 15, positions 15 and 19, or positions 19 and 23 of SEQ ID NO;
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2-20. -20. (canceled)
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21. A glucagon antagonist/GLP-1 agonist peptide, wherein the peptide comprises a derivative of the peptide of SEQ ID NO:
- 51 wherein the glucagon peptide differs from the peptide of SEQ ID NO;
51 by amino acid substitutions at one to three amino acid positions selected from positions 1, 5, 6, 8, 9, 12, 13 and 14, said peptide exhibiting at least 90% of the maximum agonism of native GLP-1 at the GLP-1 receptor, and exhibiting glucagon antagonist activity, that reduces the maximum glucagon-induced cAMP production by the glucagon receptor by at least about 80%, as measured by cAMP production in an in vitro assay.
- 51 wherein the glucagon peptide differs from the peptide of SEQ ID NO;
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22-38. -38. (canceled)
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39. A peptide comprising (1) an intramolecular bridge, or an alpha, alpha-di-substituted amino acid, or an acidic amino acid at position 16 (according to the numbering of SEQ ID NO:
- 1), or a combination thereof, (2) a C-terminal amide or ester in place of a C-terminal carboxylate, and (3) a general structure of A-B-C,
wherein A is selected from the group consisting of (i) PLA; (ii) an oxy derivative of PLA; and (iii) a peptide of 2 to 6 amino acids in which two consecutive amino acids of the peptide are linked via an ester or ether bond; wherein B represents amino acids p to 26 of SEQ ID NO;
1, wherein p is 3, 4, 5, 6, or 7, optionally comprising one or more amino acid modifications selected from the group consisting of;(iv) Asp at position 9 (according to the amino acid numbering of SEQ ID NO;
1) is substituted with a Glu, a sulfonic acid derivative of Cys, homoglutamic acid, β
-homoglutamic acid, or an alkylcarboxylate derivative of cysteine having the structure of; - View Dependent Claims (44, 45, 47, 48, 49, 52, 53, 54, 55, 57, 58, 61, 62, 63, 64, 66, 67)
- 1), or a combination thereof, (2) a C-terminal amide or ester in place of a C-terminal carboxylate, and (3) a general structure of A-B-C,
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40-43. -43. (canceled)
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46. (canceled)
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50-51. -51. (canceled)
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56. (canceled)
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59-60. -60. (canceled)
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65. (canceled)
Specification