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Chemoenzymatic tandem cyclization for the facile synthesis of bicyclic 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.

SUBMITTER: Kobayashi M

PROVIDER: S-EPMC10978974 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Chemoenzymatic tandem cyclization for the facile synthesis of bicyclic peptides.

Kobayashi Masakazu M Onozawa Naho N Matsuda Kenichi K Wakimoto Toshiyuki T

Communications chemistry 20240328 1

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 cy ...[more]

PMID: 38548970

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