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 

机构地区：[1]High Magnetic Field Laboratory,Chinese Academy of Sciences [2]School of Life Sciences,University of Science and Technology of China [3]School of Biological and Medical Engineering,Hefei University of Technology [4]Hybio Pharmaceutical Co., Ltd.

出　　处：《Chinese Chemical Letters》2018年第7期1135-1138,共4页中国化学快报（英文版）

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

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.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.

关 键 词：Linaclotide Guanylyl cyclase Protein chemical synthesis Fmoc solid phase peptide synthesis Racemic crystallization 

分 类 号：TQ464.7[化学工程—制药化工]