Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture

  1. Khushboo Bafna
  2. Kris White
  3. Balasubramanian Harish
  4. Romel Rosales
  5. Theresa A. Ramelot
  6. Thomas B. Acton
  7. Elena Moreno
  8. Thomas Kehrer
  9. Lisa Miorin
  10. Catherine A. Royer
  11. Adolfo García-Sastre
  12. Robert M. Krug
  13. Gaetano T. Montelione

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Abstract

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 M pro and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the M pro binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 M pro protease activity, while four dock well into the PL pro substrate binding cleft and inhibit PL pro protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit M pro , or both M pro and PL pro , suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold.

Highlights

  • Several HCV protease inhibitors are predicted to inhibit SARS-CoV-2 M pro and PL pro .

  • Seven HCV drugs inhibit M pro enzyme activity, four HCV drugs inhibit PL pro .

  • Seven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells.

  • HCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2.

eTOC blurb

Bafna, White and colleagues report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 M pro and/or PL pro proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold.

Abstract Figure

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    SciScore for 10.1101/2020.12.13.422511: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.12.13.422511 on bioRxiv