Insight towards the effect of the multibasic cleavage site of SARS-CoV-2 spike protein on cellular proteases

  1. Kamal Shokeen
  2. Shambhavi Pandey
  3. Manisha Shah
  4. Sachin Kumar

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Abstract

Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presents an immense global health problem. Spike (S) protein of coronavirus is the primary determinant of its entry into the host as it consists of both receptor binding and fusion domain. While tissue tropism, host range, and pathogenesis of coronavirus are primarily controlled by the interaction of S protein with the cell receptor, it is possible that proteolytic activation of S protein by host cell proteases also plays a decisive role. The host-cell proteases have shown to be involved in the proteolysis of S protein and cleaving it into two functional subunits, S1 and S2, during the maturation process. In the present study, the interaction of S protein of SARS-CoV-2 with different host proteases like furin, cathepsin B, and plasmin has been analyzed. Incorporation of the furin cleavage site (R-R-A-R) in the S protein in SARS-CoV-2 has been studied by mutating the individual amino acid. Our results suggest the polytropic nature of the S protein of SARS-CoV-2. Our analysis indicated that a single amino acid substitution in the polybasic cleavage site of S protein perturb the binding of cellular proteases. This mutation study might help to generate an attenuated SARS-CoV-2. Besides, targeting of host proteases by inhibitors may result in a practical approach to stop the cellular spread of SARS-CoV-2 and to develop its antiviral.

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    SciScore for 10.1101/2020.04.25.061507: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The sequences were aligned using the ClustalW algorithm implemented in the sequence alignment program package of MEGA-X software.
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)
    All the three-dimensional structures were visualized using PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Further, the three-dimensional structures of the mutants were generated by SWISS-MODEL protein structure homology-modeling and further validated by PROCHECK-Ramachandran plot after its energy minimization using Yasara software.
    Yasara
    suggested: (YASARA, RRID:SCR_017591)

    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.
    • 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 10.1101/2020.04.25.061507v1 on bioRxiv