Design and evaluation of GLP-1 receptor G-protein biased agonist with prolonged efficacy on diabetes.

Abstract Aim Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potent drug development target for treating diabetes and obesity. Here, we designed and evaluated novel long-acting GLP-1R G protein biased agonist with potent clinical application. Main methods GLP-1R G-protein biased sequences were screened via a high-throughput autocrine-based strategy and then fused to Exendin (9–39). These fusion peptides were further performed with site-specific modification. Surface plasmon resonance (SPR) measurements, GLP-1R activation potencies and plasma stability tests were applied to screen optimal candidate. Acute and chronic hypoglycemic and insulinotropic activities of selected agent were evaluated in diabetic and obese rodent animals. Main findings AX09 exert highest binding affinities for GLP-1R extracellular domain (GLP-1R ECD). Further in vitro plasma stability and GLP-1R activation assays demonstrated better potency of AX18. Acute pharmacodynamic evaluation of AX18 demonstrated the promising insulinotropic and hypoglycemic activities which were exhibited in a dose-dependent manner. Prolonged hypoglycemic efficacies of AX18 were also observed in both hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diabetic mice. Further pharmacokinetic test in cynomolgus monkeys exhibited that the half-life of AX18 was more than 6 days. Once weekly treatment of AX18 in diabetic mice for 8-week achieved significantly improved %HbA1C, insulin resistance, glucose tolerance, β-cells and diabetic retinal injury. Chronic treatment of AX18 in diet-induced obese (DIO) mice also exhibited beneficial efficacies on %HbA1C, inflammation-related factors lowering, and weight gains. Conclusion AX18, as a novel GLP-1R G protein biased agonist, exhibited potency for treating diabetes mellitus and its complications.