Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents

In order to develop novel long-acting GLP-1 derivatives, a peptide hybrid (1a) from human GLP-1 and Xenopus GLP-1 discovered in our previous research was selected as the lead compound. Exendin-4 inspired modification resulted in peptide 1b with enhanced glucose-lowering activity. Cysteine mutated 1b derivatives with reserved bioactivity were further site-specifically connected with mPEG2000-MAL to provide conjugates 3a–h, among which 3d and 3e were found to have significantly improved hypoglycemic activity and insulinotropic ability than GLP-1. The hypoglycemic durations of 3d and 3e were remarkably prolonged to ∼20 h in type 2 diabetic db/db mice, compared with the 5.3 h of exendin-4 in the same test. Finally, chronic in vivo studies revealed that a once-daily treatment of 3d or 3e for five weeks resulted in recovered glucose-controlling ability of type 2 diabetic db/db mice, along with other benefits, such as reduced body weight gains, food intake amounts and HbA1c values. Collectively, our results suggest 3d and 3e as potential long-acting glucose-lowering agents for treating type 2 diabetes. [Display omitted] •A human GLP-1/Xenopus GLP-1 hybrid peptide was discovered with enhanced glucose-lowering activity.•Further site-specific PEGylation identified 3d and 3e with improved hypoglycemic and insulinotropic activity than GLP-1.•The hypoglycemic durations of 3d and 3e were four times as longer as that of exentin-4 in type 2 diabetic db/db mice.•Once-daily injection of 3d or 3e achieved long-term beneficial effects in db/db mice.