Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y2 Receptor Agonists

• DOI: 10.1021/acs.jmedchem.2c01385
• Publication Date: 2022-10-10T15:06:56Z
• Authors: Qimeng Yang; Weizhong Tang; Lidan Sun; Zhiming Yan; Chunli Tang; Yongliang Yuan; Huan Zhou; Feng Zhou; Siyuan Zhou; Qingqing Wu; Peng Song; Ting Fang; Ronglian Xu; Jing Han; Neng Jiang
• Keywords: 0303 health sciences; Liraglutide; Glucagon-Like Peptide-1 Receptor; Mice; Xenopus laevis; 03 medical and health sciences; Cholesterol; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Non-alcoholic Fatty Liver Disease; Animals; Hypoglycemic Agents; Neuropeptide Y; Obesity; Triglycerides

GLP-1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2R) dual agonists have shown great potential to treat obesity and type 2 diabetes (T2DM). We developed a multitarget strategy to design monomeric agonists based on Xenopus GLP-1 (xGLP-1) and PYY3-36 analogues with dual activation activities on GLP-1R and Y2R. A novel peptide, 6q, was obtained via stepwise structure optimization and in vitro receptor screens. In db/db and diet-induced obesity (DIO) mice, 6q produced greater effects on long-term glycemic control and body weight reduction than GLP-1R and Y2R monoagonist counterparts. Notably, in high-fat diet-induced nonalcoholic steatohepatitis (NASH) mice, 6q treatment significantly reduced hepatic triglyceride and total cholesterol levels and reversed hepatic steatosis compared with GLP-1R monoagonist (liraglutide) treatment. Collectively, these data support the therapeutic potential of our GLP-1R/Y2R dual agonist 6q as a novel antidiabetic, antiobesity, and antisteatotic agent.