Journal
CHINESE CHEMICAL LETTERS
Volume 29, Issue 7, Pages 1135-1138Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cclet.2018.01.005
Keywords
Linaclotide; Guanylyl cyclase; Protein chemical synthesis; Fmoc solid phase peptide synthesis; Racemic crystallization
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Funding
- National Natural Science Foundation of China (NSFC) [21572043]
- Fundamental Research Funds for the Central Universities [PA2017GDQT0021]
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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. (C) 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
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