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

symbolscript 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 symbolscript GLP-1 (xGLP-1) and PYY3-36 analogues with dual activation activities on GLP-1R and Y2R. A novel peptide, symbolscript was obtained via stepwise structure optimization and symbolscript symbolscript receptor screens. In symbolscript and diet-induced obesity (DIO) mice, symbolscript 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, symbolscript treatment significantly reduced hepatic triglyceride and total cholesterol levels and reversed hepatic steatosis compared with GLP-1R mono-agonist (liraglutide) treatment. Collectively, these data support the therapeutic potential of our GLP-1R/Y2R dual agonist symbolscript as a novel antidiabetic, antiobesity, and antisteatotic agent.