SIRT脱ミリストイル化活性選択的阻害剤の開発と細胞機能の光操作

SIRT 去肉豆蔻酰化活性选择性抑制剂的开发和细胞功能的光操纵

• 批准号: 22K06505
• 负责人: 川口 充康
• 金额: $ 2.75万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22K06505/
• 关键词: 中分子阻害剤; SIRT2; 光異性化; Sirtuin; 中分子; 阻害剤; 光操作

近年、Sirtuin (SIRT) は「脱アセチル化活性」に加え「脱ミリストイル化活性」を示すことが明らかになり、各々の活性が異なる生理的・病理的機能を制御することも示されている。酵素サブタイプ間での選択性に加え、単一酵素内の各々の活性に対して選択性を持つ阻害剤が開発できれば、酵素機能を詳細に解明するツールになるだけでなく、副作用の少ない医薬品にも繋がる。しかし、SIRTを標的としたそのような阻害剤の開発例はない。本研究で私は、これまでの研究で見出した「脱ミリストイル化活性」に対し選択性を示すペプチド性阻害剤S2DMi-7を基に、SIRT間でのサブタイプ選択的かつ病理機能を示す酵素活性選択的に阻害する中分子化合物を開発・評価し、その創出戦略の有用性実証を目指し研究に着手した。本年においては、細胞膜透過性が乏しいことが分かっていたペプチド性SIRT2阻害剤S2DMi-7の細胞膜透過性向上を目指し、i)オクタアルギニン部位、ii)リポ酸基、iii)環状化の3つのアプローチの中で最も透過性が高まる手法の評価を行った。阻害活性評価の結果、誘導体化によりやや阻害活性の低下が認められたものの、いずれの阻害剤でも強いSIRT2阻害活性を示すことが明らかになった。また、特にオクタアルギニンや環状化阻害剤においてSIRT2を発現するHeLa細胞に対し細胞障害性を有すること、およびAc-Tubulin量を増加させることが示され、S2DMi-7に比べて格段に細胞膜透過性が高まっていることが示唆された。さらに、SIRT2により脱アセチル化されることで安定化されることが知られるBubR1のタンパク質量を評価したところ、阻害剤処理によりBubR1の分解が促進されることが明らかになった。以上より、特に環状化ペプチド性SIRT2阻害剤において細胞膜透過性が高まることが示された。

In recent years, the Sirtuin (SIRT) system "exfoliation activity" plus "desquamation activity" shows that there are significant changes in the physiology and pathology of the active cells. The enzyme machine can be used to determine whether there is an increase in the activity of each enzyme or an enzyme in each enzyme. The enzyme machine can be used to determine whether there is any adverse effect or side effect on medical products. Please tell me how to stop the damage in the SIRT environment. In this study, the results of the study showed that the molecular compounds in the enzyme activity assay were selected, and the results showed that the molecular compounds in the enzyme activity assay were selected, and the molecular compounds in the enzyme activity selection were selected. the results showed that the molecular compounds in the enzyme activity selection were selected, and the results showed that the molecular compounds in the enzyme activity selection were selected, and the results showed that the molecular compounds in the enzyme activity selection were successfully selected. This year, the cell membrane permeability test showed that SIRT2 blocked the cell membrane permeability of S2DMi-7 cells in order to improve the membrane permeability. I) the location of cell membrane permeability, ii) amino acid group, iii) the most effective method in the treatment of environmental pollution. The results of the inhibitory activity test, the low inhibitory activity, the strong SIRT2 inhibitory activity, the low inhibitory activity, the high inhibitory activity, the low inhibitory activity, the strong inhibitory activity, the low inhibitory activity, the strong inhibitory activity, the inhibitory activity. Special attention should be paid to the prevention of environmental impact on the environment. The HeLa cell barrier has been detected in the SIRT2. The cell barrier of the HeLa cell has been detected, the cell barrier of the cell has been detected by the measurement of Ac-Tubulin, and the cell membrane permeability of the cell segment has been detected. The cell membrane permeability has been detected by S2DMi-7. In order to improve the stability of the system, we need to know that there is a lot of information on the stability of SIRT2, SIRT2, BubR1, stability, stability and stability. The above-mentioned environmental and special environmental protection SIRT2 hinders the cell membrane permeability and shows that the cell membrane permeability is very high.

项目成果

Photoinduced NO-release from polymer dots doped with an Ir(<scp>iii</scp>) complex and <i>N</i>-methyl-<i>N</i>-nitroso-4-aminophenol

掺杂 Ir(<scp>iii</scp>) 络合物和 <i>N</i>-甲基-<i>N</i>-亚硝基-4-氨基苯酚的聚合物点光诱导 NO 释放

• DOI: 10.1039/d3ob00047h
• 发表时间: 2023
• 期刊: Organic &amp; Biomolecular Chemistry
• 作者: Saitoh Daisuke;Suzuki Ayumi;Ieda Naoya;Liu Zuoyue;Osakada Yasuko;Fujitsuka Mamoru;Kawaguchi Mitsuyasu;Nakagawa Hidehiko
• 通讯作者: Nakagawa Hidehiko