Discovery, evolution and potential future applications of bismuth bicycle molecules—a novel class of therapeutics with unique properties.
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.
