Oct 15, 2020Paper

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

BioRxiv : the Preprint Server for Biology
V. TiwariUmesh R. Desai

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.

Citations

Mar 27, 2021·Frontiers in Molecular Biosciences·Deling ShiLianli Chi
Mar 31, 2021·Environmental Chemistry Letters·Rossana SegretoDaoyu Zhang

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