Saan Voss , Amin Sagar , Arnaud Tiberghien , Richard J. L. Hughes , Liuhong Chen , Inmaculada Rioja , Mark Frigerio , Michael J. Skynner , David R. Spring

Journal of Peptide Science

DOI: 10.1002/psc.70071

Abstract

Bicyclic peptides are emerging as next generation therapeutics by combining the affinity and specificity of antibodies with the synthetic convenience of small molecules. Phage-encoded libraries of bicyclic peptides enable the discovery of high-affinity molecules against virtually any protein target. The generation of bicyclic peptides that advanced into clinical development involves the reaction of three cysteines in a peptide to a C₃-symmetric alkylating agent. In phage display, this chemical modification transforms a pool of conformationally flexible peptides into a library of structurally unique protein mimetics that are able to bind traditionally challenging protein surfaces like those with limited structural definition. In recent years, a new class of bicyclic peptides has emerged using a single atom-bismuth-in place of C₃-symmetric organic scaffolds, thus expanding into an unexplored chemical space at the intersection of inorganic chemistry and biology. This mini-review aims to reflect on the discovery, evolution and potential future applications of bismuth bicycle molecules.