Rational design of cyclic peptides, with an emphasis on bicyclic peptides
Catherine E Rowland, G.A. Bezerra, Michael J. Skynner
Abstract
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. • Cyclic peptides have favourable drug-like properties and broad therapeutic potential. • Rational design of peptides can include sequence, cyclisation and epitope targeting. • Structural data have been used to optimise features of multimeric Bicycle molecules. • Computational design has yielded peptide mimics of known target interactions.