Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3- O -sulfated heparan sulfate

  1. Vaibhav Tiwari
  2. Ritesh Tandon
  3. Nehru Viji Sankaranarayanan
  4. Jacob C. Beer
  5. Ellen K. Kohlmeir
  6. Michelle Swanson-Mungerson
  7. Umesh R. Desai

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Abstract

The COVID-19 pandemic caused by SARS-CoV-2 is in immediate need of an effective antidote. Although the Spike glycoprotein (SgP) of SARS-CoV-2 has been shown to bind to heparins, the structural features of this interaction, the role of a plausible heparan sulfate proteoglycan (HSPG) receptor, and the antagonism of this pathway through small molecules remain unaddressed. Using an in vitro cellular assay, we demonstrate HSPGs modified by the 3- O -sulfotransferase isoform-3, but not isoform-5, preferentially increased SgP-mediated cell-to-cell fusion in comparison to control, unmodified, wild-type HSPGs. Computational studies support preferential recognition of the receptor-binding domain of SgP by 3- O -sulfated HS sequences. Competition with either fondaparinux, a 3- O -sulfated HS-binding oligopeptide, or a synthetic, non-sugar small molecule, blocked SgP-mediated cell-to-cell fusion. Finally, the synthetic, sulfated molecule inhibited fusion of GFP-tagged pseudo SARS-CoV-2 with human 293T cells with sub-micromolar potency. Overall, overexpression of 3- O -sulfated HSPGs contribute to fusion of SARS-CoV-2, which could be effectively antagonized by a synthetic, small molecule.

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  1. Rapid Reviews Infectious Diseases

    Pyong Woo Park

    Review 1: "Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate"

    Reviewer: Pyong Woo Park (Boston Children's Hospital/Harvard Medical School) 📗📗📗📗◻️

  2. Rapid Reviews Infectious Diseases

    Pyong Woo Park

    Review of "Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate"

    Reviewer: Pyong Woo Park(Boston Children's Hospital/Harvard Medical School) 📗📗📗📗◻️

  3. ScreenIT

    SciScore for 10.1101/2020.10.08.331751: (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 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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  4. Version published to 10.1101/2020.10.08.331751v1 on bioRxiv