チアゾール含有環状ペプチドの翻訳合成法

一种含噻唑环肽的转化合成方法

基本信息

批准号：
16F16033
负责人：
菅裕明
金额：
$ 1.47万
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：
2016
资助国家：
日本
起止时间：
2016-04-22 至 2018-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16F16033/
关键词：
mRNA translation thioamide チアゾールペプチド環状ペプチド翻訳薬剤探索

项目摘要

The synthesis of proposed unnatural amino acid derivatives were attempted but failed. Therefore, focus was diverted towards the synthesis of peptides containing a backbone thioamide moiety.Ribosome-mediated thioamide bond catalysis was demonstrated four decades ago, however, the product was merely a thioamide-dipetide, which was formed in the absence of any mRNA. Since then, there has been no report on the ribosomal synthesis of peptides containing thioamide bonds. Here, we successfully demonstrated that the ribosome is capable in catalyzing the formation of a thioamide bond in an mRNA dependent fashion during peptide translation. Central to this achievement was the flexizyme technology that, for the very first time, allowed for the preparation of an amino(thio)acyl-tRNA, AlaS-tRNAGluE2. By reprogramming the genetic code in the FIT system, we synthesized peptide with a thioamide backbone. The chemical synthesis of peptides with one or more thioamide backbones has already been established; and the strategy presented here can allow for the generation of a ~10^12 membered library of peptides with one or more thioamide backbones via mRNA display platform. Therefore, in the future, a combination of mRNA display and chemical synthesis will lead to the discovery of macrocyclic thioamide-peptides with attractive biological and pharmacological properties.

尝试合成所提出的非天然氨基酸衍生物但失败了。因此，焦点转向含有主链硫代酰胺部分的肽的合成。核糖体介导的硫代酰胺键催化在四十年前就已被证明，然而，产物仅仅是硫代酰胺二肽，它是在没有任何mRNA的情况下形成的。此后，再也没有关于核糖体合成含有硫代酰胺键的肽的报道。在这里，我们成功证明了核糖体能够在肽翻译过程中以 mRNA 依赖性方式催化硫代酰胺键的形成。这一成就的核心是灵活酶技术，该技术首次允许制备氨基（硫代）酰基-tRNA，AlaS-tRNAGluE2。通过重新编程 FIT 系统中的遗传密码，我们合成了具有硫代酰胺主链的肽。具有一个或多个硫代酰胺主链的肽的化学合成方法已经建立；这里提出的策略可以允许通过 mRNA 展示平台生成具有一个或多个硫代酰胺主链的 ~10^12 成员肽库。因此，在未来，mRNA展示和化学合成的结合将导致具有有吸引力的生物学和药理学特性的大环硫代酰胺肽的发现。