Design of Xenopus GLP-1-Based Long-Acting Dual GLP-1/Y<sub>2</sub> Receptor Agonists
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
Abstract
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.