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| Chemical synthesis and structural analysis of guanylate cyclase C agonist linaclotide |
| Chenchen Chena,b, Shuai Gaoc, Qian Quc, Pengcheng Mid, Anjin Taod, Yi-Ming Lic |
a High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China;
b School of Life Sciences, University of Science and Technology of China, Hefei 230026, China;
c School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, China;
d Hybio Pharmaceutical Co., Ltd., Shenzhen 518057, China |
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| Guide 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. |
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Abstract 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.
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Received: 20 November 2017
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| Fund:This work was supported by the National Natural Science Foundation of China (NSFC No. 21572043) and the Fundamental Research Funds for the Central Universities (No. PA2017GDQT0021). |
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Corresponding Authors:
Yi-Ming Li, ymli@hfut.edu.cn
E-mail: ymli@hfut.edu.cn
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