Virus-Mediated Self-Assembly of Functional Cyclodextrins for Antiviral Inhibition

We report a virus-mediated supramolecular assembly as an adaptive inhibitor of viral infection. Building on cyclodextrin (CD) host-guest self-assembly, we designed a monomer bearing an adamantyl unit to promote inclusion-mediated polymerization, a bridge across the CD cavity to prevent self-inclusion, and a sialic acid (SA) ligand to engage spike glycan-recognition sites. A series of SA-functionalized self-assembling CDs was synthesized, together with nonassembling and nonbinding controls. In cellular infection assays, the SA-functionalized self-assembling CD inhibited SARS-CoV-2-induced cytopathic effect (CPE) without detectable cytotoxicity, whereas controls were inactive, indicating that both self-assembly and ligand recognition are required for antiviral activity. NMR and cryo-electron microscopy studies of the active SA-functionalized self-assembling CD show that the viral surface mediates supramolecular polymer growth by nucleating cooperative supramolecular polymerization through ligand-receptor recognition. Inhibition was maintained across multiple SARS-CoV-2 variants, consistent with adaptive assembly. Coassembly with an unfunctionalized self-assembling CD preserved strong inhibition at low ligand fractions, supporting heteropolymer formation with optimized ligand spacing. These findings establish virus-mediated supramolecular polymerization of functional CDs as a modular antiviral platform.