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

GLP-1 receptor (GLP-1R) and neuropeptide Y 2 receptor (Y 2 R) 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 PYY 3-36 analogues with dual activation activities on GLP-1R and Y 2 R. 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 Y 2 R 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/Y 2 R dual agonist 6q as a novel antidiabetic, antiobesity, and antisteatotic agent.