In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein. Issue 85 (24th November 2017)

• Record Type: Journal Article
• Authors: Lu, Lian; Su, Xiaoqing; Wang, Yantai; Luo, Yi; Yang, Jun; Xie, Li; Gao, Xuefeng; Ma, Yaru; Tian, Yaomei; Yuan, Fengjiao; He, Gu; Zhou, Bailing; Fan, Yingzi; Zhang, Xueyan; Huang, Rong; Lam, Ying Ka; Jiang, Lin; Dai, Hua; Zhao, Qian; Liao, Xiaoyang; Yang, Li
• Is Part Of: RSC advances. Volume 7:Issue 85(2017)
• Page Start: 54178
• Page End: 54187
• Publication Date: 2017-11-24
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7ra10822b
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : 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). Abstract : 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 U2 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.