Structural basis of SARS-CoV-2 polymerase inhibition by Favipiravir

  1. Qi Peng
  2. Ruchao Peng
  3. Bin Yuan
  4. Min Wang
  5. Jingru Zhao
  6. Lifeng Fu
  7. Jianxun Qi
  8. Yi Shi

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Abstract

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into an unprecedented global pandemic. Nucleoside analogues, such as Remdesivir and Favipiravir, can serve as the first-line broad-spectrum antiviral drugs against the newly emerging viral diseases. Recent clinical trials of these two drugs for SARS-CoV-2 treatment revealed antiviral efficacies as well as side effects with different extents 1–4 . As a pyrazine derivative, Favipiravir could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides, which may further lead to mutations in progeny RNA copies due to the non-conserved base-pairing capacity 5 . Here, we determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARS-CoV-2 in the pre-catalytic state. This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase, and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues which may explain its capacity for mimicking both adenine and guanine nucleotides. These findings shed lights on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.

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    SciScore for 10.1101/2020.10.19.345470: (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

    Software and Algorithms
    SentencesResources
    The RNA products were quantified by integrating the intensity of each band using ImageJ software.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Cryo-EM data was automatically collected using SerialEM software (http://bio3d.colorado.edu/SerialEM/).
    SerialEM
    suggested: (SerialEM, RRID:SCR_017293)
    Image processing: The movie frames were aligned using MotionCor2 to correct beam-induced motion and anisotropic magnification38.
    MotionCor2
    suggested: (MotionCor2, RRID:SCR_016499)
    The structure of FTP was built using the “Ligand builder” plug-in in COOT and manually fitted into the density.
    COOT
    suggested: (Coot, RRID:SCR_014222)
    The figure was generated with PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 15, 16, 28, 29 and 30. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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 10.1101/2020.10.19.345470 on bioRxiv