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. Firstly, a robust and versatile strategy was implemented to enable the cyclization of ribosomally derived peptide sequences <i>via </i>a chemoselective reaction between a genetically encoded cysteine and a cysteine-reactive unnatural amino acid (<i>O</i>-(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 inside bacterial cells. This 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. The thioether-bridging methodology was further implemented toward production of polycyclic structures of different connectivity, thus further expanding the scope of macrocyclic peptides produced by the ribosomal machinery directly inside living bacteria.

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

249th National Meeting (2015)

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