Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists

Dual activation of the Glucagon Receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) has the potential to lead to an effective therapy for the treatment of diabetes and obesity. Here, we report the discovery of a series of peptides with dual activity on GLP-1R and GCGR that were discovered by rational design. Structural elements of oxyntomodulin (OXM), glucagon or exendin-4 were engineered into the selective GLP-1R agonist Xenopus GLP-1 (xGLP-1) on the basis of sequence analysis, resulting in hybrid peptides with potent dual activity at GLP-1R and GCGR. Further modifications with fatty acid resulted in a novel metabolically stable peptide (xGLP/GCG-15) with enhanced and balanced GLP-1R and GCGR activations. This lead peptide was further explored pharmacologically in both db/db and diet-induced obesity (DIO) rodent models. Chronic administration of xGLP/GCG-15 significantly induced hypoglycemic effects and body weight loss, improved glucose tolerance, and normalized lipid metabolism, adiposity, and liver steatosis in relevant rodent models. These preclinical studies suggest that xGLP/GCG-15 has potential for development as a novel anti-obesity and/or anti-diabetic candidate. Considering the equal effects of xGLP/GCG-15 and the clinical candidate MEDI0382 on reverse hepatic steatosis, it may also be explored as a new therapy for nonalcoholic steatohepatitis (NASH) in the future.