title: Systematic Design of Trypsin Cleavage Site Mutated Exendin4-Cysteine 1, an Orally Bioavailable Glucagon-Like Peptide-1 Receptor Agonist.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. wenbosai@hotmail.com.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Sai
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. tinahew@139.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. ykmylx@126.com.
authors.forename: Kangmin
authors.initials: K
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. yitangchen@aliyun.com.
authors.forename: Daoqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. m15295783798@163.com.
authors.forename: Jinxiao
authors.initials: J
authors.lastname: Bao
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. 18251380528@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. xiaoda_song@126.com.
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. zhangyu2007sm@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. luorogen@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. xdgao@cpu.edu.cn.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. wbyao@cpu.edu.cn.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Yao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000737:chemistry; D005951:Glucose Tolerance Test; D007421:Intestine, Small / Q000201:enzymology; D008297:Male; D051379:Mice; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; D010447:Peptide Hydrolases; D014357:Trypsin; D003545:Cysteine; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: TSME-1; exednin-4; exendin4-cysteine; orally administered; type 2 diabetes