The Water-Soluble[60]Fullerene Derivatives as Bindersof SARS-CoV-2 Proteins

Abstract Water-soluble fullerene derivatives represent emerging molecular nanomaterials for antiviral drug discovery, yet their target selectivity against SARS-CoV-2 proteins remains insufficiently defined. Here, four functionalized [60]fullerenes, C60(OH)24, C60ser, C60ALA, and C60Trp, were evaluated as binders of key SARS-CoV-2 targets involved in viral entry and replication: spike glycoprotein, papain-like protease, 3CL main protease, and RNA-dependent RNA polymerase. Microscale thermophoresis revealed distinct target-dependent binding profiles governed by fullerene functionalization. The C60Trp fullerene was the most active derivative, binding Spike with nanomolar affinity (Kd = 94.8 nM) and showing micromolar affinity toward papain-like protease and 3CL main protease. Docking and molecular dynamics simulations supported the preferential interaction of C60Trp with the spike protein cavity through combined fullerene cage complementarity and polar interactions with lysine and arginine residues. The tested derivatives showed low cytotoxicity in A549 cells, and C60Trp was efficiently internalized. These findings identify tryptophan-functionalized [60]fullerene as a promising multivalent scaffold for SARS-CoV-2 protein targeting.