Rational design of small-sized peptidomimetic inhibitors disrupting protein-protein interaction

Protein-protein interactions are fundamental to nearly all biological processes. Due to their structural flexibility, peptides have emerged as promising candidates for developing inhibitors targeting large and planar PPI interfaces. However, their limited drug-like properties pose challenges. Hence, rational modifications based on peptide structures are anticipated to expedite the innovation of peptide-based therapeutics. This review comprehensively examines the design strategies for developing small-sized peptidomimetic inhibitors targeting PPI interfaces, which predominantly encompass two primary categories: peptidomimetics with abbreviated sequences and low molecular weights and peptidomimetics mimicking secondary structural conformations. We have also meticulously detailed several instances of designing and optimizing small-sized peptidomimetics targeting PPIs, including MLL1-WDR5, PD-1/PD-L1, and Bak/Bcl-xL, among others, to elucidate the potential application prospects of these design strategies. Hopefully, this review will provide valuable insights and inspiration for the future development of PPI small-sized peptidomimetic inhibitors in pharmaceutical research endeavors.