Cyclic peptides for protein–protein interaction targets: Applications to human disease

Protein–protein interactions (PPIs) represent a significant portion of functionally relevant biological interactions, and therefore potential therapeutic targets. Small molecules were traditionally used to target PPIs. However, many PPI surfaces lack binding pockets due to their large and flat structures. Antibodies can also be used to modulate PPIs, but they are expensive and not cell permeable. Linear peptides are less expensive to produce than antibodies and are generally more selective than small molecules, but they are limited by decreased stability and poor permeability. Modified peptides (peptidomimetics, e.g., cyclic peptides) can overcome these obstacles. Advantages of using cyclic peptidomimetics to modulate PPIs derive from their conformational constraint, which supports target specificity, cell permeability, and metabolic stability. Methods for rational design coupled with high-throughput techniques continue to support advances in the field. Further development of cyclic peptidomimetics to modulate PPIs will improve treatment of human diseases, such as cancer, infection, neurodegeneration, and autoimmunity. Here we describe several cyclic peptidomimetics that are currently used as drugs and many potential cyclic peptides PPI inhibitors in different stages of pre-clinical and clinical development. Further development of cyclic peptidomimetics to modulate PPIs will continue to improve treatment of human diseases, such as cancer, infection, neurodegeneration, and autoimmunity.