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.
Zhenming Jin   #  1  2 ,  Yao Zhao   #  1 ,  Yuan Sun   #  3 ,  Bing Zhang  1 ,  Haofeng Wang  1  4 ,  Yan Wu  3 ,  Yan Zhu  1 ,  Chen Zhu  1 ,  Tianyu Hu  1 ,  Xiaoyu Du  1  2 ,  Yinkai Duan  1 ,  Jing Yu  1 ,  Xiaobao Yang  1 ,  Xiuna Yang  1 ,  Kailin Yang  5 ,  Xiang Liu  6 ,  Luke W Guddat  7 ,  Gengfu Xiao  3 ,  Leike Zhang  8 ,  Haitao Yang  9 ,  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. [email protected].
  • 9. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • # 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 (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.

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