Protein–Linker Co-engineering for Broad-Spectrum Antiviral Development against Enveloped Viruses

Emerging and re-emerging viruses with pandemic potential pose a continuous global health threat. Broad-spectrum antivirals, if available, could serve as a critical first line of defense. Here, we present a general and simple strategy to chemically functionalize natural proteins into broad-spectrum, nontoxic antivirals. Through a one-step conjugation, proteins are modified with alkyl ligands terminated by secondary amines. These functionalized proteins exhibit potent inhibitory activity against enveloped viruses HSV-2, Influenza A H1N1, and SARS-CoV-2, with half-effective concentrations (EC50) ranging from nanomolar to micromolar levels. Efficacy improves with increased ligand density, and longer alkyl chains induce a shift from reversible (virustatic) to irreversible (virucidal) antiviral activity. Importantly, antiviral performance remains robust in complex serum environments, and the antiviral is most effective when administered prophylactically. This versatile platform is compatible with diverse protein scaffolds, offering a promising approach for rapid antiviral development against current and future viral threats.