Ribosomal Synthesis of Topologically Defined Thioisoindole-Bridged Bicyclic Peptides.

ABSTRACT: Macrocyclic peptides are promising scaffolds for drug discovery due to their structural rigidity and high target specificity. Here, we report a strategy for in vitro ribosomal translation of thioisoindole-bridged bicyclic peptides. Central to this approach is a newly developed flexizyme substrate, Ac-Ala(NtBA)^Sc-CME, which features a semicarbazone-masked 2-nicotinoyl benzaldehyde sidechain. We show that this amino acid can be efficiently charged onto tRNA with flexizyme and incorporated into ribosomal peptides using a customized flexible in vitro translation (FIT) system. The semicarbazone group can be post-translationally removed under mild conditions, triggering spontaneous intramolecular cyclization to cysteine and lysine sidechains in the same substrate to yield thioisoindol

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC12790353 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature