Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

Yangyang Zhai; Xiangshuai Zhao; Zhengjie Cui; Man Wang; Yaxin Wang; Linfeng Li; Qi Sun; Xi Yang; Debin Zeng; Ying Liu; Yuna Sun; Zhiyong Lou; Luqing Shang; Zheng Yin

doi:10.1021/acs.jmedchem.5b01013

Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

J Med Chem. 2015 Dec 10;58(23):9414-20. doi: 10.1021/acs.jmedchem.5b01013. Epub 2015 Nov 25.

Authors

Yangyang Zhai^{1

2}, Xiangshuai Zhao^{1

2}, Zhengjie Cui^{1

2}, Man Wang^{1

2}, Yaxin Wang³, Linfeng Li^{1

2}, Qi Sun⁴, Xi Yang^{1

2}, Debin Zeng^{1

2}, Ying Liu^{1

2}, Yuna Sun⁵, Zhiyong Lou³, Luqing Shang^{1

2}, Zheng Yin^{1

2}

Affiliations

¹ College of Pharmacy and State Key Laboratory of Elemento-Organic Chemistry, Nankai University , 94 Weijin Road, Nankai District, Tianjin 300071, China.
² Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin 300071, China.
³ Laboratory of Structural Biological & Ministry of Education (MOE), and Laboratory of Protein Science, School of Medicine and Life Sciences, Tsinghua University , Beijing 100084, China.
⁴ College of Chemistry, and Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal University , Wuhan 430079, China.
⁵ National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science , Beijing 100101, China.

PMID: 26571192
DOI: 10.1021/acs.jmedchem.5b01013

Abstract

Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (1S,2S,2'S,5S)-16 and (1R,2S,2'S,5S)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C(pro). Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3C Viral Proteases
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Crystallography, X-Ray
Cysteine Endopeptidases / chemistry
Cysteine Endopeptidases / metabolism
Enterovirus A, Human / drug effects*
Enterovirus A, Human / enzymology*
Enterovirus Infections / drug therapy
Enterovirus Infections / virology*
Humans
Molecular Docking Simulation
Nitriles / chemistry
Nitriles / pharmacology*
Protein Binding
Viral Proteins / antagonists & inhibitors*
Viral Proteins / chemistry
Viral Proteins / metabolism

Substances

Antiviral Agents
Nitriles
Viral Proteins
cyanohydrin
Cysteine Endopeptidases
3C Viral Proteases