Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

Protein-protein interactions (PPIs) are well-established as a class of promising drug targets for their implications in a wide range of biological processes. However, drug development toward PPIs is inevitably hampered by their flat and wide interfaces, which generally lack suitable pockets for ligand binding, rendering most PPI systems undruggable. Here, we summarized drug design strategies for developing peptide-based PPI inhibitors. Importantly, several quintessential examples toward well-established PPI targets such as Bcl-2 family members, p53-MDM2, as well as APC-Asef are presented to illustrate the detailed schemes for peptide-based PPI inhibitor development and optimizations. This review supplies a comprehensive overview of recent progresses in drug discovery targeting PPIs through peptides or peptidomimetics, and will shed light on future therapeutic agent development toward the historically intractable PPI systems.

Automated summary

This review summarizes drug design strategies for protein-protein interactions (PPIs) targeting, specifically focusing on the development of peptide-based PPI inhibitors. Examples targeting well-known PPI targets such as Bcl-2 family members, p53-MDM2, and APC-Asef are presented to illustrate detailed schemes for peptide-based PPI inhibitor development and optimization. The review provides an overview of recent advances in drug discovery targeting PPIs through peptides or peptidomimetics, offering insights into future therapeutic agent development for historically challenging PPI systems.