Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

  1. A. Shannon
  2. B. Selisko
  3. NTT Le
  4. J. Huchting
  5. F. Touret
  6. G. Piorkowski
  7. V. Fattorini
  8. F. Ferron
  9. E. Decroly
  10. C Meier
  11. B. Coutard
  12. O. Peersen
  13. B. Canard

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Abstract

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. Here we show that Favipiravir exerts an antiviral effect as a nucleotide analogue through a combination of chain termination, slowed RNA synthesis and lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.15.098731: (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.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    In vitro infection assays: Cell line: VeroE6 (ATCC CRL-1586) cells were grown in minimal essential medium (Life Technologies) with 7.5% heat-inactivated fetal calf serum (FCS), at 37 °C with 5 % CO2 with 1 % penicillin/streptomycin (PS, 5000 U.mL-1 and 5000 μg.mL-1respectively;
    VeroE6
    suggested: None
    Software and Algorithms
    SentencesResources
    The intensity of each band was quantified using the ImageQuant software (GE Healthcare)/Image Gauge (Fuji) and/or using ImageJ as implemented in the Fiji package, with background subtraction.
    ImageQuant
    suggested: (ImageQuant, RRID:SCR_014246)
    GE Healthcare)/Image
    suggested: None
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Fiji
    suggested: (Fiji, RRID:SCR_002285)
    Antiviral experiments data were analyzed using GraphPad Prism 7 software (Graph pad software)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Quasi species with frequency over 0.1% were studied.
    Quasi
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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 did not find any issues relating to the usage of bar graphs.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.05.15.098731v1 on bioRxiv