O-フタルアルデヒド基を用いたペプチドの高効率マクロ環化とその応用

邻苯二甲醛基团肽的高效大环化及其应用

• 批准号: 22KF0114
• 负责人: 菅 裕明
• 金额: $ 1.41万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2023
• 资助国家: 日本
• 起止时间: 2023-03-08 至 2025-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22KF0114/
• 关键词: RaPID; peptide cyclization; OPA; mRNA display

From Oct 2022 to Mar 2023, we aimed to investigate OPA-based technology for constructing nonstandard cyclic peptide libraries using FIT system. Due to OPA's high reactivity, we first explored 3,4-ThDA, a di-aldehyde compound with lower reactivity. Our experiments demonstrated selective cyclization with lysine and thiol-catalyzed thienopyrrole formation. This method yielded good conversion and better stability than the reported OPA chemistry, but the harsh conditions need optimization for in vitro translation.We are also working on OPA-CME derivatives for flexizyme-mediated OPA-acylated tRNA synthesis, aiming to create non-standard libraries. The OPAon/off method is being developed for controlling OPA reactivity during translation and post-translational cyclization. This strategy helps identify peptide inhibitors targeting protein kinases containing cysteine and lysine residues in the binding pockets.

从2022年10月到2023年3月，我们旨在研究基于OPA的技术，用于使用FIT系统构建非标准的环状肽库。由于OPA的高反应性，我们首先探索了3,4-THDA，这是一种反应性较低的Di-Aldededede化合物。我们的实验表明，赖氨酸和硫醇催化的硫吡咯形成选择性环化。与报道的OPA化学相比，该方法产生了良好的转化率和更好的稳定性，但是恶劣的条件需要优化体外翻译。我们还致力于用于挠性介导的OPA介导的OPA酰基化TRNA合成的OPA-CME衍生物，旨在创建非标准库。 Opaon/OFF方法正在开发用于控制翻译和翻译后环化过程中的OPA反应性。该策略有助于鉴定靶向含有含有半胱氨酸和赖氨酸残基的蛋白激酶的肽抑制剂。

项目成果

Solid-Phase-Based Synthesis of Lactazole-Like Thiopeptides

乳唑类硫肽的固相合成

• DOI: 10.1021/acs.orglett.2c02870
• 发表时间: 2022
• 期刊: Organic Letters
• 影响因子: 5.2
• 作者: Zhang Yue;Vinogradov Alexander A.;Chang Jun Shi;Goto Yuki;Suga Hiroaki
• 通讯作者: Suga Hiroaki