Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential

We here report the discovery and therapeutic efficacy of a novel series of glucagon-like peptide-1 (GLP-1) receptor agonists derived from Xenopus GLP-1. First, five amino acid-mutated Xenopus GLP-1s were synthesized, and xGLP-3 with the best acute and long-acting hypoglycemic activity was selected for further modification. Next, PEGylation of xGLP-3 was performed at specific sites, which were determined using cysteine mutagenesis scanning. Twelve PEGylated conjugates tethered with Mal-PEGs of 1, 2, and 5 kDa were synthesized. Conjugates 7b and 7c, which exhibited comparable hypoglycemic and insulinotropic effects to Gly8-GLP-1, were selected for in-depth evaluation. It was found that 7b and 7c exhibited prolonged in vivo half-life and improved pharmacokinetic behaviors. The long-term hypoglycemic effects of 7b and 7c were further confirmed by pre-OGTT and multiple OGTT. Importantly, long-term administration of 7b or 7c in db/db mice achieved beneficial effects on body weight loss, food intake and HbA1c reduction, and glucose tolerance normalization. These preclinical studies indicate the promising role of 7b and 7c as long-acting type 2 diabetes therapeutics. In addition, our research demonstrated the feasibility of developing novel antidiabetic agents based on Xenopus GLP-1.

Graphical abstractA novel series of GLP-1 receptor agonists were designed and synthesized based on Xenopus GLP-1. 7b and 7c showed prolonged glucose-lowering effect and prominent therapeutic potential on db/db mice.Download high-res image (94KB)Download full-size image