Rational design of cyclic peptides, with an emphasis on bicyclic peptides

Macrocyclic peptides are a promising chemotype for drug discovery, given their attractive properties of proteolytic stability, bioavailability and the ability to inhibit protein-protein interactions. Approaches to the generation of macrocyclic peptides include optimisation of hits from library screening; de novo design from known ligands and antibody paratopes or protein-protein interactions; constraint of linear peptides to afford beneficial properties of macrocycles; and novel approaches to cyclisation. We describe the recent literature and exemplify these approaches in the design of peptide macrocycles, and the benefits of incorporating computational and structure-guided approaches into compound design and optimisation. The benefits of the use of structural biology as a component part of phage display campaigns are further exemplified by reference to the optimisation of Bicycle® molecules.