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SARS-CoV-2 spike protein binds heparan sulfate in a length- and sequence-dependent manner

View ORCID ProfileLin Liu, View ORCID ProfilePradeep Chopra, Xiuru Li, View ORCID ProfileMargreet A. Wolfert, View ORCID ProfileS. Mark Tompkins, View ORCID ProfileGeert-Jan Boons
doi: https://doi.org/10.1101/2020.05.10.087288
Lin Liu
1Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA
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Pradeep Chopra
1Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA
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Xiuru Li
1Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA
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Margreet A. Wolfert
1Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA
3Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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S. Mark Tompkins
2Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA
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Geert-Jan Boons
1Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA
3Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
4Department of Chemistry, University of Georgia, Athens, GA 30602, USA
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  • For correspondence: G.J.H.P.Boons@uu.nl gjboons@ccrc.uga.edu
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ABSTRACT

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing an unprecedented global pandemic demanding the urgent development of therapeutic strategies. Microarray binding experiments using an extensive heparan sulfate (HS) oligosaccharide library showed the spike of SARS-CoV-2 can bind HS in a length- and sequence-dependent manner. Hexa- and octasaccharides composed of IdoA2S-GlcNS6S repeating units were identified as optimal ligands. Surface plasma resonance (SPR) showed the SARS-CoV-2 spike protein binds with higher affinity to heparin (KD 55 nM) compared to the receptor binding domain (RBD, KD 1 µM) alone. An octasaccharide composed of IdoA2S-GlcNS6S could inhibit spike-heparin interaction with an IC50 of 38 nM. Our data supports a model in which the RBD of the spike of SARS-CoV-2 confers sequence specificity for HS expressed by target cells whereas an additional HS binding site in the S1/S2 proteolytic cleavage site enhances the avidity of binding. Collectively, our results highlight the potential of using HS oligosaccharides as a therapeutic agent by inhibiting SARS-CoV-2 binding to target cells.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 10, 2020.
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SARS-CoV-2 spike protein binds heparan sulfate in a length- and sequence-dependent manner
Lin Liu, Pradeep Chopra, Xiuru Li, Margreet A. Wolfert, S. Mark Tompkins, Geert-Jan Boons
bioRxiv 2020.05.10.087288; doi: https://doi.org/10.1101/2020.05.10.087288
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SARS-CoV-2 spike protein binds heparan sulfate in a length- and sequence-dependent manner
Lin Liu, Pradeep Chopra, Xiuru Li, Margreet A. Wolfert, S. Mark Tompkins, Geert-Jan Boons
bioRxiv 2020.05.10.087288; doi: https://doi.org/10.1101/2020.05.10.087288

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