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

Abstract

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro 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.

• Authors: 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
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 27 Issue 6 Pg. 529-532 (06 2020) ISSN: 1545-9985 [Electronic] United States
• PMID: 32382072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Viral Nonstructural Proteins
• Cysteine Endopeptidases
• Coronavirus 3C Proteases
• carmofur
• Fluorouracil

Topics

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