Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as treatment options\nfor type 2 diabetes mellitus (T2DM). Here, we designed a high-throughput GLP-1R extracellular\ndomain (ECD)-based system that enabled the screening of high-potency receptor-biased GLP-1R\nagonists demonstrating new pharmacological virtues. Firstly, six 12-mer peptides (termed PEP01-06),\nscreened from a large phage displayed peptide library were fused to the N-terminus of Exendin-4\n(29-39) to generate PEP07-12. By the use of four lysine-altered PEP07 (PEP13-16) as the starting\npoint, a series of fatty chain conjugates (PEP17-20) were synthesized and evaluated by in vitro\nGLP-1R-based cell assays. In addition, the acute and long-term in vivo effects on diet-induced\nobesity (DIO) mice were further evaluated. All four conjugates showed good receptor activation\nefficacy, and PEP20 was selected to undergo further assessment. Preclinical experiments in DIO\nmice demonstrated that PEP20 had significant insulinotropic activities and glucose-lowering abilities.\nMoreover, a prolonged antidiabetic effect of PEP20 was also observed by the hypoglycemic test in\nDIO mice. Furthermore, long-term treatment with PEP20 achieved beneficial effects on the food\nintake, weight gain, hemoglobin A1C (HbA1C) lowering activity, and glucose tolerance compared\nwith the control and was similar to the Liraglutide. In conclusion, PEP20, a GLP-1R ECD-biased\nagonist, may provide a novel therapeutic approach to T2DM.
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