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

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

  • Peptides. 2023 Mar:161:170948. doi: 10.1016/j.peptides.2023.170948.
Xiaolong Zhang 1,  Yuchen Cai 2,  Zhihong Yao 3,  Heng Chi 1,  Yan Li 1,  Jingjing Shi 1,  Zhongbo Zhou 4,  Lidan Sun 5
Affiliations

Affiliations

  • 1 Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China.
  • 2 School of Engineering, China Pharmaceutical University, Nanjing 210009, Jiangsu, PR China.
  • 3 Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China.
  • 4 School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise 533000, Guangxi, PR China. Electronic address: zzb7855@163.com.
  • 5 Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China. Electronic address: slidan89@mail.zjxu.edu.cn.
PMID: 36646385 DOI: 10.1016/j.peptides.2023.170948
Abstract

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.

Keywords

Diabetes; Glucagon; Glucagon-like peptide-1; OXM; Obesity.

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