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.

2022年10月至2023年3月，研究基于opa的FIT系统构建非标准环肽库的技术。由于OPA具有较高的反应活性，我们首先探索了反应活性较低的二醛化合物3,4- thda。我们的实验证明了赖氨酸选择性环化和巯基催化噻吩吡咯形成。该方法具有较好的转化率和稳定性，但需要对条件进行优化。我们也在研究OPA-CME衍生物，用于flezimyme介导的opa -酰化tRNA合成，旨在创建非标准文库。目前正在开发opon /off方法来控制翻译和翻译后环化过程中的OPA反应性。这种策略有助于识别肽抑制剂靶向蛋白激酶含有半胱氨酸和赖氨酸残基在结合口袋。

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