Increased elastase sensitivity and decreased intramolecular interactions in the more transmissible 501Y.V1 and 501Y.V2 SARS-CoV-2 variants’ spike protein–an in silico analysis

  1. Suman Pokhrel
  2. Benjamin R. Kraemer
  3. Lucia Lee
  4. Kate Samardzic
  5. Daria Mochly-Rosen

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Abstract

Two SARS-CoV-2 variants of concern showing increased transmissibility relative to the Wuhan virus have recently been identified. Although neither variant appears to cause more severe illness nor increased risk of death, the faster spread of the virus is a major threat. Using computational tools, we found that the new SARS-CoV-2 variants may acquire an increased transmissibility by increasing the propensity of its spike protein to expose the receptor binding domain via proteolysis, perhaps by neutrophil elastase and/or via reduced intramolecular interactions that contribute to the stability of the closed conformation of spike protein. This information leads to the identification of potential treatments to avert the imminent threat of these more transmittable SARS-CoV-2 variants.

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  1. Version published to 10.1371/journal.pone.0251426
  2. ScreenIT

    SciScore for 10.1101/2021.01.19.427355: (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
    Calculating Predicted Effect of Variants in PROVEAN and SIFT: The amino acid sequence of spike protein from the index EPI_ISL_402124 (Wuhan) sequence was uploaded to PROVEAN (37) (http://provean.jcvi.org/index.php) and SIFT (38) (https://sift.bii.a-star.edu.sg).
    PROVEAN
    suggested: (PROVEAN, RRID:SCR_002182)
    Each variant was either predicted to be ‘deleterious’ or ‘neutral’ in PROVEAN or ‘deleterious’ or ‘benign’ in SIFT.
    SIFT
    suggested: (SIFT, RRID:SCR_012813)
    Multiple Sequence Alignment: MEGA X software (39) and the ClustalW alignment function was used to align the amino acid sequences of the human index, bat, civet, pangolin, 501Y.V1 and 501Y.V2 SARS-CoV-2 spike proteins.
    MEGA X
    suggested: None
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)

    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: We detected the following sentences addressing limitations in the study:
    Limitations to our analysis: Our study uses computational tools to examine the potential impact of the mutations found in SARS-CoV-2 501Y.V1 and 501Y.V2 on the viral infectivity has several limitations. We focused only on two aspects – sensitivity to protease and increased open conformer of the spike protein. Other mechanisms may increase viral transmissibility and were not examined here. For example, if proteolytic events contribute to viral inactivation at the mucosa, a decline in proteolysis susceptibility, especially to proteases present in the nose, may also contribute to increased infectivity. We also did not examine the possibility that the increased transmissibility of the new variants may be due to better survival of the virus in respiratory droplets, the potential increased affinity of the viral spike protein for receptors other than ACE2, nor the impact of mutations in other viral genes. Finally, our analysis tested mainly the potential impact of one mutation at a time. As our analysis is in silico, experiments to test the hypotheses raised by this study should be conducted next, to determine if these SARS-CoV-2 variants with more efficient and rapid transmission capabilities are also more sensitive to existing therapies and suggest new therapeutic targets to slow down and arrest the COVID-19 pandemic.

    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 17. 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.

  3. Version published to 10.1101/2021.01.19.427355v1 on bioRxiv