Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

  1. Kangsa Amporndanai
  2. Xiaoli Meng
  3. Weijuan Shang
  4. Zhenmig Jin
  5. Michael Rogers
  6. Yao Zhao
  7. Zihe Rao
  8. Zhi-Jie Liu
  9. Haitao Yang
  10. Leike Zhang
  11. Paul M. O’Neill
  12. S. Samar Hasnain

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Abstract

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M pro ), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M pro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M pro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M pro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M pro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta -corona viruses.

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  1. Version published to 10.1038/s41467-021-23313-7
  2. ScreenIT

    SciScore for 10.1101/2021.03.11.434764: (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
    For cytotoxicity assays, pre-seeded Vero E6 cells were treated with appropriate concentrations of compound.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    The IC50 was calculated by plotting the inhibition rate against various concentrations of testing inhibitor by using a four parameters dose-response curve in GraphPad Prism software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 12. 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

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  3. Version published to 10.1101/2021.03.11.434764v1 on bioRxiv