Navigating the labyrinth of drugging the disordered

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are central players in many cellular processes, which make their involvement across cellular dysregulation and diseases evident. Unlike structured proteins, they carry out their functions mainly through interactions with a variety of partners. Recent progress, from large-scale proteome studies to detailed atomic-level investigations, has shed light on how their dynamic nature shapes complex structure-function relationships. Despite this flexibility, IDPs and IDRs are also being explored as promising drug targets. However, successful therapeutic efforts first require a careful understanding of their dynamic behavior and interactions. In this review, we outline how protein disorder influences both health and disease, and highlight relentless approaches aimed at turning this flexibility into opportunities for drug discovery.