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Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease

Chunlong Ma, Michael D. Sacco, Brett Hurst, Julia A. Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael T. Marty, Yu Chen, View ORCID ProfileJun Wang
doi: https://doi.org/10.1101/2020.04.20.051581
Chunlong Ma
1Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, United States
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Michael D. Sacco
2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States
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Brett Hurst
3Institute for Antiviral Research, Utah State University, Logan, UT, 84322, USA
4Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA
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Julia A. Townsend
5Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, 85721, United States
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Yanmei Hu
1Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, United States
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Tommy Szeto
1Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, United States
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Xiujun Zhang
2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States
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Bart Tarbet
3Institute for Antiviral Research, Utah State University, Logan, UT, 84322, USA
4Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA
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Michael T. Marty
5Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, 85721, United States
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Yu Chen
2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States
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  • For correspondence: junwang@pharmacy.arizona.edu ychen1@usf.edu
Jun Wang
1Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, United States
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  • ORCID record for Jun Wang
  • For correspondence: junwang@pharmacy.arizona.edu ychen1@usf.edu
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Abstract

A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.96% as of May 4, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 μM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known Mpro inhibitors. A complex crystal structure of SARS-CoV-2 Mpro with GC-376, determined at 2.15 Å resolution with three monomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by Mpro. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.

Competing Interest Statement

J. W. and C. M. are inventors of a pending patent that claims the use of the identified compounds for COVID-19.

Footnotes

  • In this revision, we provided additional binding assay results from the native mass spectrometry as well as the X-ray crystal structure of SARS-CoV-2 in complex with GC-376.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 08, 2020.
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Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
Chunlong Ma, Michael D. Sacco, Brett Hurst, Julia A. Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael T. Marty, Yu Chen, Jun Wang
bioRxiv 2020.04.20.051581; doi: https://doi.org/10.1101/2020.04.20.051581
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Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
Chunlong Ma, Michael D. Sacco, Brett Hurst, Julia A. Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael T. Marty, Yu Chen, Jun Wang
bioRxiv 2020.04.20.051581; doi: https://doi.org/10.1101/2020.04.20.051581

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