A novel drug discovery modality inducing tagging of disease related proteins
| Project/Area Number |
18H02551
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Tohoku University (2019-2022)
The University of Tokyo (2018) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | タンパク質タグ化 / 創薬化学 / ハイブリッド分子 / タグ化 / 疾患関連タンパク質 / 翻訳後修飾 / タンパク質のタグ化 |
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| Outline of Final Research Achievements |
Here, we aimed to design and synthesis hybrid molecules by linking a disease-related protein ligand and tags (or tagging-inducing molecules), and we aimed to show that the hybrid molecules induce "tagging" of the disease-related proteins, and artificially modulate them. First, we showed that our PROTACs, which induce ubiquitination of mutant huntingtin, a cause of Huntington's disease, could be applied to other neurodegenerative proteins, and achieved brain-permeable property by chemical modification of our lead PROTACs. In addition, we developed a histidine-selective bioorthogonal reaction through joint research. Furthermore, as an application of this, we succeeded in tagging disease-related proteins using this bioorthogonal reaction.
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| Academic Significance and Societal Importance of the Research Achievements |
低分子創薬の主流は、疾患関連タンパク質のポケットに結合する阻害薬の探索であり、その機能制御が分子基盤である。しかし、この「鍵と鍵穴創薬」が通用しない疾患関連タンパク質については、創薬成功例が少ないのが実情である。このことから、新しい低分子創薬技術の開発は、チャレンジングであるが重要な学術的課題である。今回、タンパク質分解薬PROTACが複数の神経変性タンパク質を分解できることを見出し、また脳移行性を示すPROTAC類縁体も創製し、神経変性疾患に対して、タンパク質分解薬が新しい創薬手法になり得ることを提案した。また、神経変性タンパク質の化学修飾に成功し、新たな創薬手法への一歩を踏み出した。
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Report
(5 results)
Research Products
(70 results)
