Macrocyclic peptides as protein-protein interaction modulators: a review

Protein-protein interactions (PPIs) govern essential cellular processes, such as signal transduction, enzymatic catalysis, and the formation of macromolecular complexes, but their broad and dynamic interfaces often lack deep binding pockets, making it difficult for them to target conventional small molecules. Macrocyclic peptides have emerged as a powerful alternative, bridging the gap between small molecules and biologics and providing the structural flexibility for targeting extended protein surfaces with high specificity and affinity. The limitations of early efforts to modulate PPIs with linear peptides began to shift with the discovery of naturally occurring cyclic peptides and the development of phage display technologies, which demonstrated that conformational constraint could enhance the affinity and proteolytic resistance of peptides. Recent literature studies reveal a clear trend toward targeting disease-driving PPIs, particularly in oncology, such as MDM2-p53, BCL-2 family interactions, and KRAS-effector complexes, along with growing applications in infectious and inflammatory diseases. High-throughput screening technologies, structure-based drug design, and artificial intelligence techniques have facilitated the identification and prediction of novel peptide-based drugs. Various chemical modification techniques, including hydrocarbon stapling methods, cyclization from head to tail, and the addition of unnatural amino acids, have increased peptide stability and developed their capacity to cross cellular membranes. This review investigates the recently established and emerging strategies for discovering macrocyclic peptide-based PPI modulators, highlighting their application in targeting diverse diseases, thereby expanding the scope of precision medicine, and concludes with a discussion on the future directions in the field of PPI-directed peptide-based drug development.