Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2020 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2020) vom: 08. Okt. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tiwari, Vaibhav [VerfasserIn] |
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| Links: |
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| Themen: |
Antagonists |
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| Anmerkungen: |
Date Revised 19.10.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2020.10.08.331751 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316219878 |
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| 100 | 1 | |a Tiwari, Vaibhav |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate |
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| 500 | |a Date Revised 19.10.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a Antagonists | |
| 650 | 4 | |a Coronavirus | |
| 650 | 4 | |a Heparan Sulfate | |
| 650 | 4 | |a Small Molecule Inhibitor | |
| 650 | 4 | |a Spike glycoprotein | |
| 700 | 1 | |a Tandon, Ritesh |e verfasserin |4 aut | |
| 700 | 1 | |a Sankaranarayanan, Nehru Viji |e verfasserin |4 aut | |
| 700 | 1 | |a Beer, Jacob C |e verfasserin |4 aut | |
| 700 | 1 | |a Kohlmeir, Ellen K |e verfasserin |4 aut | |
| 700 | 1 | |a Swanson-Mungerson, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Desai, Umesh R |e verfasserin |4 aut | |
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