Polysulfates block SARS-CoV-2 uptake through electrostatic interactions

Nie, Chuanxiong; Pouyan, Paria; Lauster, Daniel; Trimpert, Jakob; Kerkhoff, Yannic; Szekeres, Gergo Peter; Wallert, Matthias; Block, Stephan; Sahoo, Anil Kumar; Dernedde, Jens; Pagel, Kevin; Kaufer, Benedikt B.; Roland,; Netz, R.; Ballauff, Matthias; Haag, Rainer

doi:10.1002/anie.202102717

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Polysulfates block SARS-CoV-2 uptake through electrostatic interactions

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Sahoo, Anil Kumar
Richard Weinkamer, Biomaterialien, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

Nie, C., Pouyan, P., Lauster, D., Trimpert, J., Kerkhoff, Y., Szekeres, G. P., et al. (2021). Polysulfates block SARS-CoV-2 uptake through electrostatic interactions. Angewandte Chemie International Edition, 60(29), 15870-15878. doi:10.1002/anie.202102717.

Cite as: https://hdl.handle.net/21.11116/0000-0008-1CB4-E

Abstract

Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC₅₀) of 67 μg/mL (approx.1.6 μM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC₅₀: 4084μg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even morewith the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2.