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

• 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

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.

有人试图合成拟议的非天然氨基酸衍生物，但失败了。核糖体介导的硫代酰胺键催化作用早在40年前就被证明，然而，产物仅仅是硫代酰胺二肽，它是在没有任何信使核糖核酸的情况下形成的。从那时起，就没有关于含有硫代酰胺键的多肽的核糖体合成的报道。在这里，我们成功地证明了在肽翻译过程中，核糖体能够以一种依赖于mRNA的方式催化硫代酰胺键的形成。这一成就的核心是Flexizyme技术，该技术首次允许制备氨基(硫代)酰基tRNA，唉-tRNAGluE2。通过对FIT系统中的遗传密码进行重新编程，我们合成了带有硫代酰胺骨架的多肽。具有一个或多个硫代酰胺骨架的多肽的化学合成已经建立，该策略可以通过mRNA展示平台建立具有一个或多个硫酰胺骨架的~10^12个成员的多肽文库。因此，在未来，mRNA展示和化学合成的结合将导致发现具有诱人的生物学和药理性质的大环硫酰胺-多肽。

项目成果

Center for Molecular Biology, Hyderabad(India)

分子生物学中心，海得拉巴（印度）

東京大学大学院理学系研究科化学専攻菅研究室ホームページ

东京大学研究生院理学研究科化学系须贺实验室主页

Ribosome-Mediated Site-Specific Incorporation of Dipeptides and Dipeptidomimetics into Proteins

核糖体介导的二肽和二肽模拟物位点特异性掺入蛋白质

• 发表时间: 2016
• 作者: Rumit Maini