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

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are vital for cellular processes but are largely untapped therapeutic targets.
• Despite over 650,000 estimated human PPIs, inhibitors exist for only 117 (∼0.02%).

Purpose of the Study:

• To review existing inhibitors of human PPIs.
• To classify PPIs based on their interface's dominant secondary structure (α-helix, β-strand, disordered/loop).
• To link interface topology to effective inhibitor discovery strategies.

Main Methods:

• Literature review of human PPIs and their inhibitors.
• Classification of PPIs by interface secondary structure.
• Analysis of successful structure-guided inhibitor discovery approaches.

Main Results:

• α-Helical interfaces are the most common for reported PPI inhibitors.
• β-Strand-mediated and disordered/loop interactions are underexplored despite their significance.
• Structure-guided methods like rational peptide design and fragment-based screening are key to success.

Conclusions:

• Classifying PPIs by interface structure provides a framework for inhibitor development.
• Challenges remain for targets like coiled-coil interactions and intrinsically disordered regions.
• Emerging technologies like cryo-EM and AI will accelerate the discovery of novel PPI therapeutics.