Macrocyclic Peptides as Protein-Protein Interaction Modulators: A Review

Abstract

Protein-protein interactions (PPIs) are essential for cellular function, mediating processes such as signal transduction, enzymatic catalysis, and the formation of macromolecular complexes. PPIs are crucial for targeting therapeutics, as disruptions in these interactions can result in many diseases. However, the dynamic nature of PPIs and their broad interaction surfaces lead to challenges for drug development. Peptides, in particular macrocyclic peptides, offer a promising approach due to their synthetic availability, high specificity, and ability to bind to "undruggable" protein surfaces. Macrocyclic peptides are notable for their potency, stability, and selectivity in inhibiting PPIs, making them suitable candidates for refinement in traditional drug development.These peptides can be customised to improve biophysical properties such as binding affinity, selectivity, and resistance to degradation, thereby increasing their therapeutic potential for specific diseases. Screening methods enable the identification of macrocyclic peptides that can precisely target broad, flat protein surfaces, similar to antibody-based therapies, thus overcoming the limitations of small-molecule drugs. This review investigates established and emerging strategies for discovering macrocyclic peptide-based PPI modulators, highlighting their application in targeting diverse diseases and concluding with a discussion on the future directions of this field.