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 Liao; Li Yang

doi:10.1039/c7ra10822b

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

5 Citations (SciVal)

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 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 language	English
Pages (from-to)	54178-54187
Number of pages	10
Journal	RSC Advances
Volume	7
Issue number	85
Early online date	24 Nov 2017
DOIs	https://doi.org/10.1039/c7ra10822b
Publication status	Published - 2017

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1039/c7ra10822bLicence: CC BY

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Lu, L., Su, X., Wang, Y., Luo, Y., Yang, J., Xie, L., Gao, X., Ma, Y., Tian, Y., Yuan, F., He, G., Zhou, B., Fan, Y., Zhang, X., Huang, R., Lam, Y. K., Jiang, L., Dai, H., Zhao, Q., ... Yang, L. (2017). In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4-Fc fusion protein. RSC Advances, 7(85), 54178-54187. https://doi.org/10.1039/c7ra10822b

Lu, L, Su, X, Wang, Y, Luo, Y, Yang, J, Xie, L, Gao, X, Ma, Y, Tian, Y, Yuan, F, He, G, Zhou, B, Fan, Y, Zhang, X, Huang, R, Lam, YK, Jiang, L, Dai, H, Zhao, Q, Liao, X & Yang, L 2017, 'In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4-Fc fusion protein', RSC Advances, vol. 7, no. 85, pp. 54178-54187. https://doi.org/10.1039/c7ra10822b

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

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.",

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

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doi = "10.1039/c7ra10822b",

language = "English",

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T1 - In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4-Fc fusion protein

AU - Lu, Lian

AU - Su, Xiaoqing

AU - Wang, Yantai

AU - Luo, Yi

AU - Yang, Jun

AU - Xie, Li

AU - Gao, Xuefeng

AU - Ma, Yaru

AU - Tian, Yaomei

AU - Yuan, Fengjiao

AU - He, Gu

AU - Zhou, Bailing

AU - Fan, Yingzi

AU - Zhang, Xueyan

AU - Huang, Rong

AU - Lam, Ying Ka

AU - Jiang, Lin

AU - Dai, Hua

AU - Zhao, Qian

AU - Liao, Xiaoyang

AU - Yang, Li

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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DO - 10.1039/c7ra10822b

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

Abstract

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