Chemical synthesis and structural analysis of guanylate cyclase C agonist linaclotide

作     者：Chenchen Chen Shuai Gao Qian Qu Pengcheng Mi Anjin Tao Yi-Ming Li 

作者机构：High Magnetic Field LaboratoryChinese Academy of Sciences School of Life SciencesUniversity of Science and Technology of China School of Biological and Medical EngineeringHefei University of Technology Hybio Pharmaceutical Co. Ltd. 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2018年第29卷第7期

页      面：1135-1138页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100705[医学-微生物与生化药学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (NSFC No. 21572043) the Fundamental Research Funds for the Central Universities (No. PA2017GDQT0021) 

主　　题：Linaclotide Guanylyl cyclase Protein chemical synthesis Fmoc solid phase peptide synthesis Racemic crystallization 

摘      要：Guanylate cyclase C(GC-C) is an important receptor protein expressed by intestinal epithelial cells, and its dysregulation leads to severe intestinal diseases. Linaclotide is a 14-amino acid peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation(IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Drug molecule design based on structural information plays a crucial role and the activity of linaclotide still need to improve, while the structure of linaclotide remains unknown. In this work, linaclotide and its D-enantiomer were obtained through Fmoc solid phase peptide synthesis method and co-crystalized through racemic crystallization. The crystal structure showed that linaclotide has a tight, three-beta turns structure immobilized by three pairs of disulfide bonds.