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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) 📗📗📗📗◻️

Published onApr 14, 2022
Review 1: "Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate"
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Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-<i>O</i>-sulfated heparan sulfate

AbstractThe 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.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This is an interesting study that shows that heparan sulfate proteoglycans (HSPGs) modified by 3-O-sulfotransferase 3B (3OST-3B), but not 3OST-5, enhance SARS-CoV-2 Spike glycoprotein (SgP)-mediated cell-cell fusion. The authors also show that fondaparinux and SPGG, a highly sulfated synthetic small molecule, inhibit SgP-mediated cell-cell fusion. Based on these data, they conclude that overexpression of 3-O-sulfated HSPGs contributes to the fusion of SARS-CoV-2 and that this interaction could be effectively antagonized by a small, synthetic molecule. The evidence provided is reliable and potentially significant. Results from this study are in agreement with other studies suggesting the importance of cell surface HSPGs in SARS-CoV-2 infection. Importantly, this study adds new knowledge that a particular sulfate modification (i.e., 3-O-sulfation) of HS might be important for SARS-CoV-2 infection, and suggests that blocking HSPG interactions might be a viable therapeutic option. A minor concern is that while the expression studies clearly demonstrate the specificity of 3OSTs in generating the 3-O-sulfated microdomain that mediates SgP-mediated cell-cell fusion, the inhibition studies do not clearly confirm this. In other words, the expression studies clearly indicate that not all 3-O-sulfated HSPGs bind to SgP, but this is not further pursued in inhibition studies with heparan compounds modified by 3OST-3B and 3OST-5. In essence, the potent inhibitory effects seen with increasing doses of SPGG might even refute the importance of 3-O-sulfated HS microdomains in SARS-CoV-2 infection. I think the biological impact of the study could be strengthened by showing that HS isolated from CHO-K1 cells expressing 3OST-3B inhibits SgP-mediated cell-cell fusion, whereas HS from CHO-K1 cells or CHO-K1 cells expressing 3OST-5 does not. Alternatively, the authors could discuss in more detail how inhibition with fondaparinux and SPGG relate mechanistically to the finding that select 3OSTs generate the 3-O-sulfated microdomain in HS that mediates SgP-mediated cell-cell fusion. Also, if known, a short discussion on the expression profile of the 3OST isoforms in the normal and diseased lungs would also help readers appreciate the importance of 3-O-sulfated HS microdomains.

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