1. Chemoenzymatic tandem cyclization for the facile synthesis of bicyclic peptides.
- Author
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Kobayashi, Masakazu, Onozawa, Naho, Matsuda, Kenichi, and Wakimoto, Toshiyuki
- Subjects
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PEPTIDE synthesis , *RING formation (Chemistry) , *COPPER , *DEPSIPEPTIDES , *MEMBRANE permeability (Biology) , *CHEMORECEPTORS , *PEPTIDES - Abstract
Bicyclic peptides exhibit improved metabolic stabilities and target specificities when compared to their linear or mono-cyclic counterparts; however, efficient and straightforward synthesis remains challenging due to their intricate architectures. Here, we present a highly selective and operationally simple one-pot chemoenzymatic tandem cyclization approach to synthesize bicyclic peptides with small to medium ring sizes. Penicillin-binding protein-type thioesterases (PBP-type TEs) efficiently cyclized azide/alkyne-containing peptides in a head-to-tail manner. Successive copper (I)-catalyzed azide-alkyne cycloaddition generated bicyclic peptides in one-pot, thus omitting the purification of monocyclic intermediates. This chemoenzymatic strategy enabled the facile synthesis of bicyclic peptides bearing hexa-, octa-, and undecapeptidyl head-to-tail cyclic scaffolds. Bicyclic peptides exhibit improved metabolic stabilities, membrane permeabilities, and target specificities over their linear and mono-cyclic counterparts, however, efficient bicyclization remains challenging. Here, the authors develop a one-pot tandem chemoenzymatic bicyclization by combination of penicillin-binding protein-type thioesterase-mediated head-to-tail macrolactamization and copper(I)-catalyzed azide–alkyne cycloaddition. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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