Structural basis for repurpose and design of nucleoside drugs for treating COVID-19

  1. Wanchao Yin
  2. Xiaodong Luan
  3. Zhihai Li
  4. Yuanchao Xie
  5. Ziwei Zhou
  6. Jia Liu
  7. Minqi Gao
  8. Xiaoxi Wang
  9. Fulai Zhou
  10. Qingxia Wang
  11. Qingxing Wang
  12. Dandan Shen
  13. Yan Zhang
  14. Guanghui Tian
  15. Haji A. Aisa
  16. Tianwen Hu
  17. Daibao Wei
  18. Yi Jiang
  19. Gengfu Xiao
  20. Hualiang Jiang
  21. Leike Zhang
  22. Xuekui Yu
  23. Jingshan Shen
  24. Shuyang Zhang
  25. H. Eric Xu

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Abstract

SARS-CoV-2 has caused a global pandemic of COVID-19 that urgently needs an effective treatment. Nucleoside analog drugs including favipiravir have been repurposed for COVID-19 despite of unclear mechanism of their inhibition of the viral RNA polymerase (RdRp). Here we report the cryo-EM structures of the viral RdRp in complex with favipiravir and two other nucleoside inhibitor drugs ribavirin and penciclovir. Ribavirin and the ribosylated form of favipiravir share a similar ribose scaffold that is distinct from penciclovir. However, the structures reveal that all three inhibitors are covalently linked to the primer strand in a monophosphate form despite the different chemical scaffolds between favipiravir and penciclovir. Surprisingly, the base moieties of these inhibitors can form mismatched pairs with the template strand. Moreover, in view of the clinical disadvantages of remdesivir mainly associated with its prodrug form, we designed several orally-available remdesivir parent nucleoside derivatives, including VV16 that showed 5-fold more potent than remdesivir in inhibition of viral replication. Together, these results demonstrate an unexpected promiscuity of the viral RNA polymerase and provide a basis for repurpose and design of nucleotide analog drugs for COVID-19.

Cryo-EM structures of the RNA polymerase of SARS-CoV-2 reveals the basis for repurposing of old nucleotide drugs to treat COVID-19.

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    SciScore for 10.1101/2020.11.01.363812: (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: 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 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 40, 33, 41 and 39. 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.

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  2. Version published to 10.1101/2020.11.01.363812v1 on bioRxiv