Drug targeting of protein-nucleic acid interactions

Protein–nucleic acid interactions are vital to gene regulation and disease, yet have long been considered “undruggable.” Recent advances are reshaping this paradigm, enabling therapeutic targeting of DNA- and RNA-binding proteins. In this review, we highlight four major strategies: (1) direct disruption of protein-nucleic acid binding, (2) stabilization of specific complexes or conformations, (3) targeted degradation of interaction partners, and (4) allosteric modulation. We explore key examples across transcription factors, RNA-binding proteins, and DNA repair proteins, and emphasize emerging chemical, structural, and computational techniques that are accelerating discovery. Together, by intervening directly in the gene regulatory machinery, these approaches expand the druggable genome and open new avenues for treating cancer, genetic disorders, and viral infections. • Protein–nucleic acid interactions, once “undruggable,” are now emerging drug targets. • Main strategies: disruption, stabilization, degradation, and allosteric modulation. • Transcription factors, RNA-binding proteins, and DNA repair proteins are targeted. • Structural and computational tools accelerate the discovery of ligands.