Structural basis for the inhibition of the SARS-CoV-2 RNA-dependent RNA polymerase by favipiravir-RTP

  1. Katerina Naydenova
  2. Kyle W. Muir
  3. Long-Fei Wu
  4. Ziguo Zhang
  5. Francesca Coscia
  6. Mathew J. Peet
  7. Pablo Castro-Hartmann
  8. Pu Qian
  9. Kasim Sader
  10. Kyle Dent
  11. Dari Kimanius
  12. John D. Sutherland
  13. Jan Löwe
  14. David Barford
  15. Christopher J. Russo

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The RNA polymerase inhibitor, favipiravir, is currently in clinical trials as a treatment for infection with SARS-CoV-2, despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, non-productive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.10.21.347690: (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

    Experimental Models: Organisms/Strains
    SentencesResources
    The atomic model was built based on a previously published atomic model of the nsp12-nsp7-nsp8 complex bound to RNA and remdesivir-RTP (PDB-7BV2) [10], with manual model building in Coot [25, 26], and real-space refinement in Phenix [27].
    remdesivir-RTP (PDB-7BV2)
    suggested: None
    Software and Algorithms
    SentencesResources
    All data were processed in RELION 3.1 [20], using particle picks imported from crYOLO 1.5 [21] (Fig.
    RELION
    suggested: (RELION, RRID:SCR_016274)
    The atomic model was built based on a previously published atomic model of the nsp12-nsp7-nsp8 complex bound to RNA and remdesivir-RTP (PDB-7BV2) [10], with manual model building in Coot [25, 26], and real-space refinement in Phenix [27].
    Coot
    suggested: (Coot, RRID:SCR_014222)
    Phenix
    suggested: (Phenix, RRID:SCR_014224)

    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 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 10.1101/2020.10.21.347690v1 on bioRxiv