Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur

Zhenming Jin; Yao Zhao; Yuan Sun; Bing Zhang; Haofeng Wang; Yan Wu; Yan Zhu; Chen Zhu; Tianyu Hu; Xiaoyu Du; Yinkai Duan; Jing Yu; Xiaobao Yang; Xiuna Yang; Kailin Yang; Xiang Liu; Luke W Guddat; Gengfu Xiao; Leike Zhang; Haitao Yang; Zihe Rao

doi:10.1038/s41594-020-0440-6

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur

Nat Struct Mol Biol. 2020 Jun;27(6):529-532. doi: 10.1038/s41594-020-0440-6. Epub 2020 May 7.

Authors

Zhenming Jin^#^{1

2}, Yao Zhao^#¹, Yuan Sun^#³, Bing Zhang¹, Haofeng Wang^{1

4}, Yan Wu³, Yan Zhu¹, Chen Zhu¹, Tianyu Hu¹, Xiaoyu Du^{1

2}, Yinkai Duan¹, Jing Yu¹, Xiaobao Yang¹, Xiuna Yang¹, Kailin Yang⁵, Xiang Liu⁶, Luke W Guddat⁷, Gengfu Xiao³, Leike Zhang⁸, Haitao Yang⁹, Zihe Rao^{1

2

6}

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
² Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China.
³ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
⁴ School of Life Sciences, Tianjin University, Tianjin, China.
⁵ Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
⁶ State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin, China.
⁷ School of Chemistry and Molecular Biosciences, the University of Queensland, Brisbane, Australia.
⁸ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China. zhangleike@wh.iov.cn.
⁹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yanght@shanghaitech.edu.cn.

^# Contributed equally.

PMID: 32382072
DOI: 10.1038/s41594-020-0440-6

Abstract

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (M^pro). Here, the X-ray crystal structure of M^pro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC₅₀ = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.

Publication types

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

MeSH terms

Animals
Betacoronavirus / drug effects
Betacoronavirus / enzymology*
COVID-19
Chlorocebus aethiops
Coronavirus 3C Proteases
Coronavirus Infections / virology
Cysteine Endopeptidases / chemistry*
Cysteine Endopeptidases / genetics
Cysteine Endopeptidases / metabolism
Fluorouracil / analogs & derivatives*
Fluorouracil / chemistry
Fluorouracil / pharmacology
Models, Molecular
Pandemics
Pneumonia, Viral / virology
SARS-CoV-2
Vero Cells
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / chemistry*
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism

Substances

Viral Nonstructural Proteins
Cysteine Endopeptidases
Coronavirus 3C Proteases
carmofur
Fluorouracil