Protein-protein interaction inhibitors in the human proteome: lessons from 117 targeted interactions

Protein-protein interactions (PPIs) orchestrate cellular function yet remain largely underexploited as therapeutic targets. Although the human interactome is estimated to contain more than 650 000 PPIs, only 117 interactions (∼0.02%) have reported inhibitors. Here, we review human PPIs with peptide, peptidomimetic, small-molecule and antibody inhibitors, and classify them according to the dominant secondary structure at the interaction interface. This framework separates PPIs into α-helix-, β-strand- and disordered/loop-mediated interactions, revealing clear links between interface topology and inhibitor discovery strategies. α-Helical interfaces account for most reported inhibitors, whereas β-strand-mediated and dynamic interactions remain comparatively underexplored despite their biological importance. Across structural classes, successful inhibitor discovery has been enabled by structure-guided approaches, including rational peptide design, macrocyclisation, fragment-based screening and peptide-directed ligand design. However, progress remains slow for challenging targets, particularly coiled-coil interactions and intrinsically disordered regions. Emerging technologies, including cryo-electron microscopy and machine learning-guided structure prediction, are rapidly expanding access to these targets. By connecting interface architecture with optimal inhibitor modality and discovery strategy, this review provides a framework for accelerating the development of next-generation PPI therapeutics.