Engineering a potent and long-acting GLP-1/Y2 receptor dual agonist as a multi-agonist therapy for diabetes and obesity.

Novel dual agonists for the glucagon-like peptide-1 (GLP-1) and Y2 receptor hold the potential for enhanced efficacy over GLP-1 receptor (GLP-1R) agonists in treating obesity and diabetes. In this study, we aimed to improve the stability and increase the drug development success rate of our previously identified GLP-1/Y2 receptor dual agonist, 6q. To achieve this, we first optimized the structure of the linker within 6q. Additionally, we explored various fatty acid albumin binders to further enhance the stability of 6q. These binders were mainly selected from approved or clinically developed GLP-1R agonists or GLP-1-based multi-agonists. Through this process, we were able to identify a lead peptide, xGLP/PYY-6, that exhibited comparable in vitro potency toward the GLP-1 and Y2 receptors as 6q but with significantly improved stability compared to 6q. In Kunming and DIO mice, xGLP/PYY-6 showed a comparable hypoglycemic effect to semaglutide, and a significantly better effect on inhibiting food intake than semaglutide. In a chronic study in DIO mice, xGLP/PYY-6 exhibited significant metabolic benefits, as reflected by regulation of lipid levels, improved glucose tolerance, weight loss, decreased hepatocellular vacuolation, and the reversal of steatosis effects caused by xGLP/PYY-6. These results indicate the potential of developing xGLP/PYY-6 as an antiobesity, lipid regulation, antisteatotic, and antidiabetic agent.