In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4-Fc fusion proteinElectronic supplementary information (ESI) available. See DOI: 10.1039/c7ra10822b

Exendin-4 (Ex-4), one of the important glucagon-like peptide-1 receptor (GLP-1R) agonists, has proven to be an effective antidiabetic agent for type 2 diabetes (T2D). However, its therapeutic potential is limited due to its short half-life ( t 1/2 ), which is subcutaneously administered twice daily. The aim of this study is to develop a safe, efficacious and longer acting potential anti-diabetic agent. The bioactivity of (Ex-4) 2 -Fc was examined in U 2 OS cells and we used molecular docking software to test the stability of the (Ex-4) 2 -Fc/GLP-1 receptor complexes. The pharmacokinetics of (Ex-4) 2 -Fc was studied in male Sprague-Dawley (SD) rats and the pharmacodynamics was assessed in various mouse models. The bioactivity of (Ex-4) 2 -Fc was over 10-fold higher than that of Ex-4-Fc in vitro and the stability of the (Ex-4) 2 -Fc/GLP-1 receptor complexes was better than that of the Ex-4-Fc/GLP-1 receptor complexes. The pharmacokinetics of (Ex-4) 2 -Fc showed that it had a more than 200-fold prolongation in plasma half-life compared with that of Ex-4, which was 122 h and 0.56 h, respectively. The treatment with (Ex-4) 2 -Fc every 6 days, compared to the vehicle control, effectively reduced body weight, decreased food intake, and improved glucose metabolism in high-fat-diet induced obesity (DIO) mice, leptin-deficient ob/ob and leptin receptor-defective db/db mice. Our studies suggest that (Ex-4) 2 -Fc retains the bioactivity of the GLP-1 receptor agonist with a prolonged half-life in vivo , providing a promising drug candidate for the treatment of type 2 diabetes. Exendin-4 (Ex-4), one of the important glucagon-like peptide-1 receptor (GLP-1R) agonists, has proven to be an effective antidiabetic agent for type 2 diabetes (T2D).