Polysulfates Block SARS-CoV-2 Uptake via Electrostatic Interactions

Abstract

Here we report that\nnegatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via\nelectrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by\nheparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched\npolyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor,\nwith a half-maximal inhibitory concentration (IC50) of 67 μg/mL (approx. 1.6 μM). This\nsynthetic polysulfates exhibit more than 60-fold higher virus inhibitory\nactivity than heparin (IC50: 4084 μg/mL), along\nwith much lower anticoagulant activity. Furthermore, in molecular dynamics\nsimulations, we verified that LPGS can bind stronger to the spike protein than\nheparin, and that LPGS can interact even more with the spike protein of the new\nN501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into\nhost cells can be blocked via electrostatic interaction, therefore LPGS can serve\nas a blueprint for the design of novel viral inhibitors of SARS-CoV-2.