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系统构建非标准环肽文库。由于OPA的高反应性，我们首先探索了3，4-ThDA，一种具有较低反应性的二醛化合物。我们的实验证明了选择性环化与赖氨酸和硫醇催化噻吩并吡咯形成。该方法比已报道的OPA化学方法具有良好的转化率和更好的稳定性，但其苛刻的条件需要优化以进行体外翻译。我们还在研究用于flexizyme介导的OPA酰化tRNA合成的OPA-CME衍生物，旨在创建非标准文库。正在开发OPAon/off方法来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结合口袋中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