title: Ribosomal Synthesis of Thioether-Bridged Bicyclic Peptides.
abstract: Many biologically active peptides found in nature exhibit a bicyclic structure wherein a head-to-tail cyclic backbone is further constrained by an intramolecular linkage connecting two side chains of the peptide. Accordingly, methods to access macrocyclic peptides sharing this overall topology could be of significant value toward the discovery of new functional entities and bioactive compounds. With this goal in mind, we recently developed a strategy for enabling the biosynthesis of thioether-bridged bicyclic peptides in living bacterial cells. This method involves a split intein-catalyzed head-to-tail cyclization of a ribosomally produced precursor peptide, combined with inter-sidechain cross-linking through a genetically encoded cysteine-reactive amino acid. This approach can be applied to direct the formation of structurally diverse bicyclic peptides with high efficiency and selectivity in living Escherichia coli cells and provides a platform for the generation of combinatorial libraries of genetically encoded bicyclic peptides for screening purposes.
authors.affiliation: Department of Chemistry, University of Rochester, 416 Hutchison Hall, RC Box 270216, 120 Trustee Road, Rochester, NY, 14627, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Bionda
authors.affiliation: Department of Chemistry, University of Rochester, 416 Hutchison Hall, RC Box 270216, 120 Trustee Road, Rochester, NY, 14627, USA. rfasan@UR.rochester.edu.
authors.forename: Rudi
authors.initials: R
authors.lastname: Fasan
mesh_terms: D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D013440:Sulfides / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D010456:Peptides, Cyclic; D013440:Sulfides
keywords: Amber stop codon suppression; Bicyclic peptides; Split intein; Thioether-linked peptide macrocycles; Unnatural amino acid