In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4-Fc fusion protein

Lian Lu, Xiaoqing Su, Yantai Wang, Yi Luo, Jun Yang, Li Xie, Xuefeng Gao, Yaru Ma, Yaomei Tian, Fengjiao Yuan, Gu He, Bailing Zhou, Yingzi Fan, Xueyan Zhang, Rong Huang, Ying Ka Lam, Lin Jiang, Hua Dai, Qian Zhao, Xiaoyang LiaoLi Yang

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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 (t1/2), 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 U2OS 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.

Original languageEnglish
Pages (from-to)54178-54187
Number of pages10
JournalRSC Advances
Volume7
Issue number85
Early online date24 Nov 2017
DOIs
Publication statusPublished - 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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