RNP interfaces as regulatory "active sites": a repurposing strategy for small molecules targeting viral 5'-untranslated regions.

RNA-protein (RNP) complexes regulate nearly every stage of gene expression and play central roles in viral infection and human disease. Despite decades of research, relatively few small molecules (SMs) have been shown to modulate RNP assemblies with mechanistic understanding. A major challenge in targeting RNA arises from the absence of well-defined SM binding pockets analogous to the catalytic active sites that guide conventional protein-directed drug discovery. However, in many biological contexts, RNP interfaces function as the effective "active sites" of regulatory RNA, where RNA structure and protein recognition surfaces converge to regulate gene expression. In this Perspective, we argue that the major obstacle to therapeutic progress is the difficulty of identifying functionally and structurally characterized RNP interfaces within highly dynamic regulatory networks. To address this challenge, we propose an integrative discovery framework centered on RNP interfaces that integrates state-of-the-art structure prediction, molecular dynamics simulations, ensemble-based virtual screening, and orthogonal biophysical validation to enable rational repurposing of FDA approved SMs. Viral