Nature-inspired macrocyclic peptides: Discovery and molecular engineering for drug development.

Abstract

Natural cyclic peptides have long served as a rich reservoir of bioactivity, occupying a unique region of the drug space that bridges the gap between small molecules and large biologics. Evolution has perfected the macrocyclic architecture to achieve exceptional target specificity and metabolic stability, providing a structural blueprint that allows these molecules to engage extended protein surfaces often inaccessible to conventional drugs. While early landmarks like cyclosporin A demonstrated the power of chameleonicity, the ability to adapt conformations to different environments - the field is currently undergoing a paradigm shift. Nature is no longer viewed merely as a source of lead compounds to be mined, but as a conceptual framework for de novo design. By integrating natural principles such as conformational constraint and amide-masking with cutting-edge technologies like mRNA display (e.g. RaPID) and artificial intelligence, researchers are now rationally engineering next-generation macrocycles, positioning them at the frontier of modern drug development.