Functionalized Fullerene for Inhibition of SARS‐CoV‐2 Variants

As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C60 fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS‐CoV‐2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS‐CoV‐2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS‐CoV‐2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All‐atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously. Fullerene functionalized with linear polyglycerol sulfate is investigated as a possible SARS‐CoV‐2 inhibitor. Fullerene interacts with soluble accessible hydrophobic portions of the viral spike protein while sulfated polyglycerol acts as a multivalent inhibitor to SARS‐CoV‐2. Functionalized fullerene shows significant viral inhibition in plaque reduction assays. Possible mechanism of inhibition is supported by docking studies, molecular dynamics simulation, and microscale thermophoresis.