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[Preprint]. 2020 May 10:2020.05.10.087288. [Version 1] doi: 10.1101/2020.05.10.087288

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
PMCID: PMC7263551  PMID: 32511404

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 (K D 55 nM) compared to the receptor binding domain (RBD, K D 1 µM) alone. An octasaccharide composed of IdoA2S-GlcNS6S could inhibit spike-heparin interaction with an IC 50 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.

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