Glucagon/GLP-1 receptor co-agonists
First Claim
1. A glucagon peptide comprising an amino acid at position 10 which is acylated or alkylated with a C4 to C30 fatty acid;
- and an α
, α
-disubstituted amino acid at position 16 of the glucagon peptide or an intramolecular bridge between 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, wherein the amino acid sequence of the glucagon peptide differs from SEQ ID NO;
1 by no more than ten amino acid modifications.
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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 intramolecular 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, acylation, alkylation, substitution of carboxy terminal amino acids, C-terminal truncation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).
74 Citations
20 Claims
-
1. A glucagon peptide comprising an amino acid at position 10 which is acylated or alkylated with a C4 to C30 fatty acid;
- and an α
, α
-disubstituted amino acid at position 16 of the glucagon peptide or an intramolecular bridge between 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, wherein the amino acid sequence of the glucagon peptide differs from SEQ ID NO;
1 by no more than ten amino acid modifications. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
- and an α
-
2. A glucagon peptide that differs from SEQ ID NO:
- 1 by no more than ten amino acid modifications, comprising an amino isobutyric acid (AIB) at position 16 and an acyl group or alkyl group covalently linked to the amino acid at position 10 of the glucagon peptide, wherein said glucagon peptide exhibits enhanced activity at the GLP-1 receptor as compared to native glucagon.
Specification