Non-native glucagon peptides with enhanced activity at the glp-1 receptor and pharmaceutical compositions comprising the same

摘要

Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. These modified glucagon co-agonist analogs may be combined with other anti-diabetic or anti-obesity compounds and used to control hyperglycemia, or to induce weight loss or prevent weight gain. In one embodiment the modified glucagon peptides comprise lactam bridges or substitution of the terminal carboxylic acid with an amide group. 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 (KRNRNNIA) and SEQ ID NO: 28 (KRNR). Use of a glucagon/GLP-1 co-agonist for administration in combination with an anti-diabetic agent or anti-obesity agent.