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J Mol Recognit. 2016 Nov;29(11):520-527. doi: 10.1002/jmr.2551. Epub 2016 May 17.

Optimize the interactions at S4 with efficient inhibitors targeting 3C proteinase from enterovirus 71.

Author information

1
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
2
State Key Laboratory on Lead Compound Research, WuXi AppTech Co., Ltd., Shanghai, 200131, China.
3
Xianmen Center for Disease Control and Prevention, Shen-guang Road 681-685, Xiamen, 361021, China.
4
Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361001, China.
5
Fujian University for Traditional Chinese Medicine, Fuzhou, 350004, China.
6
State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China.
7
State Key Laboratory on Lead Compound Research, WuXi AppTech Co., Ltd., Shanghai, 200131, China. jian_li@wuxiapptec.com.
8
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. twlin@xmu.edu.cn.

Abstract

Enterovirus 71 (EV71) is the causative agent of hand, foot and mouth disease and can spread its infections to the central nervous and other systems with severe consequences. The replication of EV71 depends on its 3C proteinase (3Cpro ), a significant drug target. By X-ray crystallography and functional assays, the interactions between inhibitors and EV71 3Cpro were evaluated. It was shown that improved interactions at S4 for the substrate binding could significantly enhance the potency. A new series of potent inhibitors with high ligand efficiency was generated for developing antivirals to treat and control the EV71-associated diseases.

KEYWORDS:

3C proteinase; cysteine protease; drug design and development; drug interaction; enterovirus 71; hand, foot and mouth disease

PMID:
27185390
DOI:
10.1002/jmr.2551
[Indexed for MEDLINE]

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