Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists.

Xiaolong Zhang, Yuchen Cai, Zhihong Yao, Heng Chi, Yan Li, Jingjing Shi, Zhongbo Zhou, Lidan Sun

Peptides 2023 Mar

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Novel glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have improved efficacy over GLP-1R mono-agonists in treating type 2 diabetes (T2DM) and obesity. Here, we describe the discovery of a novel oxyntomodulin (OXM) based GLP-1R/GCGR dual agonist with potent and balanced potency toward GLP-1R and GCGR. The lead peptide OXM-7 was obtained via stepwise rational design and long-acting modification. In ICR and db/db mice, OXM-7 exhibited prominent acute and long-acting hypoglycemic effects. In diet-induced obesity (DIO) mice, twice-daily administration of OXM-7 produced significant weight loss, normalized lipid metabolism, and improved glucose control. In DIO-nonalcoholic steatohepatitis (NASH) mice, OXM-7 treatment significantly reversed hepatic steatosis, and reduced serum and hepatic lipid levels. These preclinical data suggest the therapeutic potential of OXM-7 as a novel anti-diabetic, anti-steatotic and/or anti-obesity agent. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Xiaolong Zhang, Yuchen Cai, Zhihong Yao, Heng Chi, Yan Li, Jingjing Shi, Zhongbo Zhou, Lidan Sun. Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists. Peptides. 2023 Mar;161:170948