Small cyclic peptides have become the modality of choice for many drug development programs, particularly in cases where the molecular target(s) are not amenable to approaches using small molecules or monoclonal antibodies. This is due to their potential for very high target affinity and selectivity, and their unique pharmacokinetic profiles. Moreover, modern display screening techniques allow the rapid identification of cyclic peptide ligands to most protein targets. This has led to an explosion in the number of known cyclic peptides targeting proteins of interest over the last 5 years.
As a comparatively new modality, the binding modes of cyclic peptides to their respective targets remain relatively unexplored. Recent findings demonstrate that cyclic peptides can bind to the same binding pocket through the adoption of highly divergent structures, and can, in some cases, be highly “pre-ordered” before binding. Further, because they bind to structured domains (rather than epitopes), cyclic peptides can act as “conformational sensors” and can therefore demonstrate greater specificity than antibodies in some contexts. Perhaps most strikingly, a number of examples are now emerging of cyclic peptides that act as “molecular glues” that stabilise specific protein-protein interactions, opening the door to potential therapeutic applications that would previously have been considered impossible. Specific examples demonstrating each of these principles will be presented.