ペプチドセレクションによる酵素ミミック創薬のための戦略

使用肽选择的酶模拟药物发现策略

• 批准号: 18F18727
• 负责人: 菅 裕明
• 金额: $ 0.77万
• 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: 2018
• 资助国家: 日本
• 起止时间: 2018-07-25 至 2019-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18F18727/
• 关键词: FIT system; Foldamers; Macrocyclic peptides

This work has harvested the potential of flexizymes (artificial aminoacylation ribozymes) coupled to an in vitro translation system (the “flexible” in vitro translation system, FIT), led to the ribosomal incorporation of the largest and bulkiest residues to date. Briefly, foldamers -molecules with a strong tendency to adopt a folded conformation- composed of aromatic oligoamides have been recently proven capable of initiating translation, yielding the first-of-their-kind foldamer-peptide-hybrids. In our current work, we expanded the repertoire of foldamer functionalities and have demonstrated that side-chain modification of the helical structures grants access to previously inaccessible chemical and structural space. The incorporation of both the bulkiest and largest single residues that have been introduced by the ribosome has been demonstrated. Additionally, intrigued by the ribosomal tolerance towards aromatic oligoamides during translation initiation, we advanced our investigations and explored the possibility of incorporating these abiotic molecules as appendages during translation elongation. Our results indicated that the incorporation of an amino acid residue with a foldamer on the side-chain, as long as a heptapeptide, is feasible. It demonstrates for the first time the tolerance of the ribosome towards residues of that size and expands the current understanding on the limitations of the translational machinery. The above studies have paved the way towards the introduction of foldamers into mRNA display for the discovery of functional foldamer-peptide hybrids.

这项工作已经收获了flexizymes（人工氨酰化核酶）耦合到体外翻译系统（“灵活的”体外翻译系统，FIT）的潜力，导致核糖体掺入的最大和最笨重的残基。简而言之，最近已经证明由芳香族低聚酰胺组成的折叠体-具有采用折叠构象的强烈倾向的分子-能够引发翻译，产生第一种折叠体-肽-杂合体。在我们目前的工作中，我们扩展了折叠体功能的库，并证明了螺旋结构的侧链修饰赠款进入以前无法进入的化学和结构空间。已经证明了由核糖体引入的最大和最大的单个残基的掺入。此外，感兴趣的核糖体耐受性对芳香族低聚酰胺在翻译起始期间，我们推进了我们的调查，并探讨了将这些非生物分子作为附件在翻译延伸的可能性。我们的结果表明，在侧链上掺入一个氨基酸残基与一个折叠体，只要一个七肽，是可行的。它首次证明了核糖体对这种大小的残基的耐受性，并扩展了目前对翻译机制局限性的理解。上述研究为将折叠体引入mRNA展示中以发现功能性折叠体-肽杂合体铺平了道路。

项目成果

Ribosomally synthesized foldamer-containing peptides

核糖体合成的含折叠体的肽

• 发表时间: 2018
• 作者: Hirose H;Tsiamantas C;Katoh T;Suga H.;Tsiamantas Christos;Tsiamantas Christos
• 通讯作者: Tsiamantas Christos

In Vitro Translated Peptide-Foldamer Hybrid Macrocycles

体外翻译的肽-折叠体杂化大环化合物

• 发表时间: 2018
• 作者: Hirose H;Tsiamantas C;Katoh T;Suga H.;Tsiamantas Christos;Tsiamantas Christos;Tsiamantas Christos
• 通讯作者: Tsiamantas Christos

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

In Vitro Selection of aromatic oligoamide foldamers

芳香族低聚酰胺折叠体的体外选择

• 发表时间: 2018
• 作者: Hirose H;Tsiamantas C;Katoh T;Suga H.;Tsiamantas Christos
• 通讯作者: Tsiamantas Christos

Ludwig Maximilian University of Munich(ドイツ)

慕尼黑路德维希马克西米利安大学（德国）