Protein-Protein Interaction Inhibitors in the Human Proteome: Lessons from 117 Targeted Interactions.

Hyde, Ellie E. and Beekman, Andrew M. ORCID: https://orcid.org/0000-0002-3056-6406 (2026) Protein-Protein Interaction Inhibitors in the Human Proteome: Lessons from 117 Targeted Interactions. RSC Medicinal Chemistry, 17 (9). pp. 3930-3946. ISSN 2632-8682

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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.

Item Type:	Article
Additional Information:	Data availability: The data that support the information in this review article are found within the citations detailed in the reference list.
Uncontrolled Keywords:	das in place,data availability the data that support the information in this review article are found within the citations detailed in the reference list.,2026 ,/dt/atira/pure/keyword/DAStatement/das_in_place
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Science > Research Groups > Synthetic and Medicinal Chemistry
Related URLs:	https://doi.org/10.1039/D6MD00552G
Depositing User:	LivePure Connector
Date Deposited:	06 Nov 2026 10:51
Last Modified:	06 Nov 2026 20:01
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104992
DOI:

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