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Development of a C-Terminal Site-Specific PEGylated Analog of GLP-1 with Improved Anti-Diabetic Effects in Diabetic Mice

Authors

  • Mingming Gao,

    1. State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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    • Both authors contributed equally to this work.
  • Yue Tong,

    1. State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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    • Both authors contributed equally to this work.
  • Xiangdong Gao,

    Corresponding author
    • State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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  • Wenbing Yao

    Corresponding author
    • State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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Correspondence to: Xiangdong Gao and Wenbing Yao, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.

E-mail: xiangdong_gao@yahoo.com.cn; wbyao@cpu.edu.cn

Abstract

Preclinical Research

Glucagon-like peptide-1 (GLP-1) is an attractive lead for antidiabetic drug development but its utility is limited due to poor in vivo stability. In this study, we developed a C-terminal site-specific PEGylated analog of GLP-1 based on the structure-activity relationship of GLP-1. Using three steps of chromatography, we obtained the conjugate with a high purity. Polyethylene glycol (PEG) conjugation greatly enhanced GLP-1 potency in vivo without changing its original conformation. In streptozotosin diabetic mice, this conjugate had an improved antidiabetic effect, as measured by fasting glucose/insulin/glycosylated serum protein, oral glucose tolerance test, and histochemical studies. Additionally, this PEG-conjugated peptide delayed gastric emptying without significant effects on body weight gain. Our data indicate that this conjugate may be a promising lead for the development of antidiabetic drugs.

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