Zhang Hua, Wei Hui-Min, Xue Jun-Hao, Xia Zhe-Min, Zheng Feng-Hao, Wan Xiao-Cui, Zhou Li, Fang Ge-Min
Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, P. R. China.
High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, P. R. China.
Chembiochem. 2025 Jun 16;26(12):e202500240. doi: 10.1002/cbic.202500240. Epub 2025 Apr 21.
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.
本研究描述了一种基于连接酶的两步策略，用于制备一种独特类型的含有苄基苯基硫醚臂的双环肽分子。与传统的双环肽构建方法不同，本研究首先利用肽连接酶（Sortase A或OaAEP1）将芳基硫醇基团引入亲本肽中，然后使用TBMB进行肽的双环化反应，以生成所需的双环肽。由于芳基硫醇的pKa低于烷基硫醇，我们体系中肽的双环化反应可以在低浓度的TBMB或低pH条件下发生。低浓度的TBMB对噬菌体感染性影响很小，这将有助于维持噬菌体展示环肽的多样性。本研究建立了一种用于制备双环肽的生物相容性连接酶介导的两步策略，该策略在生物活性环肽配体的发现中具有潜在应用。
