Influenza A virus (IAV) continues to pose a major global health threat due to seasonal epidemics, pandemic potential, and the rapid emergence of antiviral resistance. Current vaccines and antivirals show variable efficacy and are limited by viral evolution, underscoring the need for new antiviral strategies that are both broadly effective and resistant to mutational escape.
Here, we explore an RNA-targeted therapeutic strategy using PROTACs—heterobifunctional molecules designed to induce proteasomal degradation of RNA-binding proteins. We have developed PROTACs comprising an E3 ligase ligand (E3LL) conjugated to an RNA moiety, enabling binding to IAV RdRp and promoting its proteasomal degradation. Our preliminary data demonstrate that these PROTACs promote E3LL recruitment to viral RdRp in infected cells and reduce viral RdRp subunit levels; this effect is abolished in E3LL-silenced cells, indicating a E3LL-mediated degradation mechanism. Ongoing studies focus on evaluating antiviral activity through quantification of viral RNA levels and infectious titers in physiologically relevant human airway epithelium models. In parallel, serial passaging experiments will assess the potential emergence of resistance mutations in RdRp.
Together, this work establishes a proof of concept for targeting conserved viral RNA–protein interactions via induced protein degradation and highlights such molecules as a promising platform for next-generation, virus-specific antiviral therapeutics.