A Ligase-Based Two-Step Approach for the Generation of Bicyclic Peptides Containing a Benzylphenyl Thioether Framework.

Abstract

This study describes a ligase-based two-step strategy to prepare a unique type of bicyclic peptide molecules containing a benzyl phenyl thioether arm. Different from the conventional bicyclic peptide construction method, this study first utilizes peptide ligases (SrtA or OaAEP1) to introduce an arylthiol group into the parent peptides and then performs bicyclization of the peptides by using TBMB to generate the desired bicyclic peptides. Since the pKa of aryl thiols is lower than that of alkyl thiols, the bicyclization reaction of the peptides in our system can occur under low concentrations of TBMB or low pH conditions. The low concentrations of TBMB have little effect on the phage infectivity, which will help maintain the diversity of phage-displayed cyclic peptides. This study establishes a biocompatible ligase-mediated two-step strategy for the preparation of bicyclic peptides, which has potential applications in the discovery of bioactive cyclic peptide ligands.