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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. Copyright © 2020 Elsevier Masson SAS. All rights reserved.


Neng Jiang, Lin Jing, Qing Li, Sibiao Su, Qimeng Yang, Feng Zhou, Xinyu Chen, Jing Han, Chunli Tang, Weizhong Tang. Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists. European journal of medicinal chemistry. 2021 Feb 15;212:113118

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PMID: 33422984

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