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.
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Acknowledgments
This work was supported by the US National Institutes of Health (grant R21 CA187502). MS instrumentation was supported by the US National Science Foundation (grants CHE-0840410 and CHE-0946653).
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Bionda, N., Fasan, R. (2017). Ribosomal Synthesis of Thioether-Bridged Bicyclic Peptides. In: Mootz, H. (eds) Split Inteins. Methods in Molecular Biology, vol 1495. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6451-2_5
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DOI: https://doi.org/10.1007/978-1-4939-6451-2_5
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