Nb-PROTAC Enables a Broad-Spectrum Breakthrough Against Influenza A

Influenza A viruses remain a persistent global health challenge, driven by rapid mutation and the frequent emergence of drug resistance. Traditional antiviral strategies, which primarily rely on functional inhibition of viral proteins, are often limited by viral evolution.

A recent study introduces a nanobody-based proteolysis-targeting chimera (Nb-PROTAC) strategy that shifts the paradigm from inhibition to targeted viral protein degradation.

By fusing NP-specific nanobodies with the VHL E3 ligase component, the engineered system directly induces degradation of the highly conserved influenza nucleoprotein (NP), offering a fundamentally new antiviral modality.

This approach demonstrates several key advances:

✔️Broad, pan-subtype degradation of NP across all 16 influenza A subtypes (H1–H16) ✔️Strong suppression of viral replication, including H1N1, H3N2, H5N1, H7N9, and H9N2 ✔️In vivo efficacy using AAV-LungM3 delivery, achieving 90% survival in H1N1 and 80% in H5N1 lethal infection models ✔️Mechanistic involvement of the autophagy–lysosome pathway, with OPTN contributing to the degradation process

Taken together, Nb-PROTAC represents a modular and programmable antiviral platform, with strong potential for developing broad-spectrum therapies against rapidly evolving viral pathogens.

Discover more: https://www.nature.com/articles/s41392-026-02666-9