Polysulfates Block SARS‐CoV‐2 Uptake through Electrostatic Interactions**

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 an IC50 of 67 μg mL−1 (approx. 1.6 μm). This synthetic polysulfate exhibits more than 60‐fold higher virus inhibitory activity than heparin (IC50: 4084 μg mL−1), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind more strongly to the spike protein than heparin, and that LPGS can interact even more with 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 interactions, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS‐CoV‐2.

Charge Matters: Mutations in Omicron Variant Favor Binding to Cells

“…[21] Other details about the model building, force-field parameters and the simulation protocol used are the same as given in our earlier publication on the SARS-CoV-2 inhibition by polysulfates. [5] Electrostatic potential maps of RBDs were calculated using the APBS tool [22] and visualized using VMD. [23] Simulation snapshots were rendered using VMD.…”

“…[4] Inhibition studies by highly charged polyelectrolytes provide another proof for the importance of charge-charge interaction for binding. [5] Thus, highly charged synthetic polyelectrolytes can compete with the HSPG and block the first step of virus infection as shown in Figure 1a. Hence, the first two steps of the process of virus uptake into cells can be envisioned as shown in Figure 1c: In step 1 the spike proteins on the surface of the virion are attached to the HSPG by strong charge-charge interaction between the negatively charged polysulfate and the positively charged amino acids on the spike protein.…”

DNA Aptamers Block the Receptor Binding Domain at the Spike Protein of SARS-CoV-2

“…It has been recently reported (Nie et al, 2021) that small molecules with negatively charged groups, such as polysulphates, can bind to the S-protein via electrostatic interactions. The strong binding occurs in that case at the "cationic patch" of the RBD, namely ARG346, ARG355, LYS444, ARG466, and ARG509.…”

Phospholipids dock SARS-CoV-2 spike protein via hydrophobic interactions: a minimal in-silico study of lecithin nasal spray therapy

“…It remains to be investigated in controlled clinical studies whether lecithin-based therapies may contribute to improve therapeutic measures, reduce infections and improve containment of the enduring COVID-19 pandemic. Another area that deserves attention are the role of mutants [ 106 , 107 ] in how they may change the binding affinity of putative blockers of SARS-CoV-2 RBD. The mechanisms of the efficiency of POPC action on mutants is beyond the scope of this paper, yet we can only speculate that mutants that enhance the exposure of hydrophobic groups in the RBD domain may enhance the binding of POPC.…”