Glucagon/GLP-1 receptor co-agonists

摘要

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).

主权项

1. A pegylated glucagon peptide of the following structure: wherein “Peptide” comprises the following sequence:(SEQ ID NO: 588)X1SQGT FTSDY SKYLD ERRAK DFVC*W LMNTa wherein: “X1” is alpha, alpha-dimethyl imidazole acetic acid; “C*” is a Cysteine residue on the glucagon peptide having a thiol which is connected to a polyethylene glycol of about 20 kD or about 40 kD average weight; “a” is a C-terminal amide; and further wherein there is a lactam bridge between amino acids 16 and 20 of the Peptide; or a pharmaceutically acceptable salt thereof.