Develpoment of inhibitors for endo-nuclease activity of influenza viruses
| Project/Area Number |
24590548
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | Chiba University |
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Principal Investigator |
HOSHINO Tyuji 千葉大学, 薬学研究科(研究院), 准教授 (90257220)
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| Co-Investigator(Renkei-kenkyūsha) |
YAMAMOTO Norio 順天堂大学, 大学院医学研究科, 准教授 (40323703)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 阻害剤 / 薬物スクリーニング / X線結晶構造解析 / 計算機シミュレーション / インフルエンザ / ポリメラーゼ / エンドヌクレアーゼ活性 / 共結晶解析 / スクリーニング / 薬物設計 / 有機合成 / 抗ウイルス活性 / 結合構造 / 計算機解析 / 共結晶構造解析 / ウイルス / 医薬品設計 / 活性測定 / ヘマグルチニン |
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| Outline of Final Research Achievements |
The endonuclease activity which lies in influenza polymerase acidic protein N-terminal domain (PAN) is a potent target for novel antiviral agents. We identified some novel inhibitors for PAN endonuclease activity. The binding mode of the inhibitory compounds to PAN was closely investigated by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of the inhibitor were bound to one PAN. Hence, the stability of inhibitor binding was examined by performing 100 ns MD simulation. During the MD simulation, three inhibitor molecules fluctuated at the respective binding site while all the molecules maintained interactions with the protein. MM/GBSA analysis suggested that the molecule located apart from the metal chelated site has a higher affinity than the others. Structural information of this study will provide a hint for designing and developing potent agents against influenza viruses.
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] Mechanism of drug resistance of hemagglutinin of influenza virus and potent scaffolds inhibiting its function2012
Author(s)
H. Yanagita, N. Yamamoto, H. Fuji, X. Liu, M. Ogata, M. Yokota, H. Takaku, H. Hasegawa, T. Odagiri, M. Tashiro, T. Hoshino
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Journal Title
ACS Chemical Biology
Volume: 7
Issue: 3
Pages: 552-562
DOI
Related Report
Peer Reviewed
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[Journal Article] Structural Modulation Study of Inhibitory Compounds for RNase H Activity of HIV-1 Reverse Transcriptase2012
Author(s)
H. Yanagita, S. Fudo, E. Urano, R. Ichikawa, M. Ogata, M. Yokota, T. Murakami, H. Wu, J. Chiba, J. Komano, T. Hoshino
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Journal Title
Chemical and Pharmaceutical Bulletin
Volume: 60
Pages: 764-771
Related Report
Peer Reviewed
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