Targeting viral proteins using insulin-like growth factor 2-fused lysosomal targeting chimera platform to combat viral infection.

Targeted protein degradation (TPD) enables selective elimination of disease-related proteins, including viral proteins. Here, we evaluated the antiviral potential of an IGF2-fused lysosomal targeting chimera (iLYTAC) in ZIKV- and IAV-infected models. We first confirmed that iLYTAC efficiently mediates uptake of extracellular proteins via the IGF2-IGF2R pathway and traffics to lysosomes. In combination with anti-E-cadherin antibody, iLYTAC reduced E-cadherin levels by 2-fold, indicating functional lysosomal targeting. For antiviral application, iLYTAC combined with non-neutralizing anti-ZIKV E IgG significantly reduced viral titers (106.25 to 105.05 PFU/mL), decreased viral RNA and protein levels, and promoted lysosomal colocalization of E protein, which was abolished by lysosome inhibition. In ZIKV-infected mice, iLYTAC combined with anti-E IgG reduced viral loads across tissues and blood, alleviated organ pathology and inflammation. Similarly, in H1N1-infected A549 cells, iLYTAC with non-neutralizing anti-HA IgG reduced cytopathic effects and viral titers, while selectively degrading HA via lysosomes without affecting NP. Overall, iLYTAC converts non-neutralizing antibodies into functional degraders of viral proteins, enabling effective suppression of infection and providing a potential platform for broad-spectrum antiviral therapeutics.