Targeted Protein and RNA Degradation as an Emerging Strategy in Antiviral Drug Discovery

Recently, protein degraders such as Proteolysis Targeting Chimeras (PROTACs) are gaining traction as valuable alternatives to traditional small-molecule inhibitors of various proteins, especially kinases implicated in cancers. PROTACs are heterobifunctional ligands that bind to the protein of interest while recruiting the cellular ubiquitin-proteasomal system to induce the selective degradation of the bound protein. By being catalytic in nature, PROTACs shift the focus from traditional occupancy-driven inhibition, thereby achieving protein degradation at lower and safer doses. Additionally, PROTACs have also found success over small-molecule inhibitors in targeting drug-resistant and undruggable protein targets. While initially developed for proteins of oncological and immunological interest, recent advances, albeit to a lesser extent, have expanded Targeted Protein Degradation (TPD) technology into the antiviral research space. Generally, research has focused on achieving antiviral effect by degrading either viral proteins or host proteins essential to virus survival. Herein, the general principles and recent advances of small-molecule-based degraders (for proteins or RNA) are summarized along with their applications in the field of antiviral drug discovery. While several limitations need to be addressed, the remarkable progress and expansion of protein degraders to the antiviral field is paving the way for a promising new modality of antiviral therapy.