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

## TL;DR

Researchers developed a simple method to turn natural proteins into broad-spectrum antivirals effective against multiple viruses, including HSV-2, Influenza A, and SARS-CoV-2.

## Contribution

A one-step conjugation strategy to functionalize proteins into nontoxic, broad-spectrum antivirals with tunable virucidal activity.

## Key findings

- Functionalized proteins showed potent antiviral activity against HSV-2, Influenza A H1N1, and SARS-CoV-2 with EC50 values in the nanomolar to micromolar range.
- Higher ligand density and longer alkyl chains increased antiviral efficacy and shifted activity from virustatic to virucidal.
- Antiviral performance remained effective in complex serum environments and was most effective when used prophylactically.

## Abstract

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.