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

Abstract

ABSTRACT 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.