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Bioinspired strategy for the ribosomal synthesis of thioether-bridged macrocyclic peptides in bacteria.

ABSTRACT: Inspired by the biosynthetic logic of lanthipeptide natural products, a new methodology was developed to direct the ribosomal synthesis of macrocyclic peptides constrained by an intramolecular thioether bond. As a first step, a robust and versatile strategy was implemented to enable the cyclization of ribosomally derived peptide sequences via a chemoselective reaction between a genetically encoded cysteine and a cysteine-reactive unnatural amino acid (O-(2-bromoethyl)-tyrosine). Combination of this approach with intein-catalyzed protein splicing furnished an efficient route to achieve the spontaneous, post-translational formation of structurally diverse macrocyclic peptides in bacterial cells. The present peptide cyclization strategy was also found to be amenable to integration with split intein-mediated circular ligation, resulting in the intracellular synthesis of conformationally constrained peptides featuring a bicyclic architecture.

SUBMITTER: Bionda N

PROVIDER: S-EPMC4168796 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Bioinspired strategy for the ribosomal synthesis of thioether-bridged macrocyclic peptides in bacteria.

Bionda Nina N Cryan Abby L AL Fasan Rudi R

ACS chemical biology 20140801 9

Inspired by the biosynthetic logic of lanthipeptide natural products, a new methodology was developed to direct the ribosomal synthesis of macrocyclic peptides constrained by an intramolecular thioether bond. As a first step, a robust and versatile strategy was implemented to enable the cyclization of ribosomally derived peptide sequences via a chemoselective reaction between a genetically encoded cysteine and a cysteine-reactive unnatural amino acid (O-(2-bromoethyl)-tyrosine). Combination of t ...[more]

PMID: 25079213

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