Modelling how the altered usage of cell entry pathways by the SARS-CoV-2 Omicron variant may affect the efficacy and synergy of TMPRSS2 and Cathepsin B/L inhibitors

  1. Pranesh Padmanabhan
  2. Narendra M. Dixit

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Abstract

The SARS-CoV-2 Omicron variant harbours mutations in its spike protein, which may affect its cell entry, tropism, and response to interventions. To elucidate these effects, we developed a mathematical model of SARS-CoV-2 entry into cells and applied it to analyse recent in vitro data. SARS-CoV-2 enters cells using host proteases, either Cathepsin B/L or TMPRSS2. We estimated >4-fold increase and >3-fold decrease in entry efficiency using Cathepsin B/L and TMPRSS2, respectively, of the Omicron variant relative to the original or other strains in a cell type-dependent manner. Our model predicted that Cathepsin B/L inhibitors would be more and TMPRSS2 inhibitors less efficacious against the Omicron than the original strain. Furthermore, the two inhibitor classes would exhibit synergy, although the drug concentrations maximizing synergy would have to be tailored to the Omicron variant. These findings provide insights into the cell entry mechanisms of the Omicron variant and have implications for interventions.

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  1. Version published to 10.1101/2022.01.13.476267v3 on bioRxiv
  2. Version published to 10.1101/2022.01.13.476267v2 on bioRxiv
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    SciScore for 10.1101/2022.01.13.476267: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot 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 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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  4. Version published to 10.1101/2022.01.13.476267v1 on bioRxiv