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Int. J. Mol. Sci. 2017, 18(3), 578; doi:10.3390/ijms18030578

Systematic Design of Trypsin Cleavage Site Mutated Exendin4-Cysteine 1, an Orally Bioavailable Glucagon-Like Peptide-1 Receptor Agonist

Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Academic Editor: Cheorl-Ho Kim
Received: 15 December 2016 / Revised: 26 February 2017 / Accepted: 2 March 2017 / Published: 8 March 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Exendin-4 is a strong therapeutic candidate for the treatment of metabolic syndrome. Related receptor agonist drugs have been on the market since 2005. However, technical limitations and the pain caused by subcutaneous injection have severely limited patient compliance. The goal of the study is to investigate a biologically active exendin-4 analog could be administered orally. Using intraperitoneal glucose tolerance tests, we discovered that exendin4-cysteine administered by oral gavage had a distinct hypoglycemic effect in C57BL/6J mice. Using Rosetta Design and Amber, we designed and screened a series of exendin4-cysteine analogs to identify those that retained biological activity while resisting trypsin digestion. Trypsin Cleavage Site Mutated Exendin4-cysteine 1 (TSME-1), an analog whose bioactivity was similar to exendin-4 and was almost completely resistant to trypsin, was screened out. In addition, TSME-1 significantly normalized the blood glucose levels and the availability of TSME-1 was significantly higher than that of exendin-4 and exendin4-cysteine. Collectively orally administered TSME-1, a trypsin-resistant exendin-4 analog obtained by the system, is a strong candidate for future treatments of type 2 diabetes. View Full-Text
Keywords: exednin-4; exendin4-cysteine; orally administered; TSME-1; type 2 diabetes exednin-4; exendin4-cysteine; orally administered; TSME-1; type 2 diabetes

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Sai, W.; Tian, H.; Yang, K.; Tang, D.; Bao, J.; Ge, Y.; Song, X.; Zhang, Y.; Luo, C.; Gao, X.; Yao, W. Systematic Design of Trypsin Cleavage Site Mutated Exendin4-Cysteine 1, an Orally Bioavailable Glucagon-Like Peptide-1 Receptor Agonist. Int. J. Mol. Sci. 2017, 18, 578.

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