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

Abstract

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.