Develpoment of inhibitors for endo-nuclease activity of influenza viruses

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590548
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Chiba University
• Principal Investigator: HOSHINO Tyuji 千葉大学, 薬学研究科(研究院), 准教授 (90257220)
• Co-Investigator(Renkei-kenkyūsha): YAMAMOTO Norio 順天堂大学, 大学院医学研究科, 准教授 (40323703)
• Project Period (FY): 2012-04-01 – 2015-03-31
• 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

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.

Free Research Field

ウイルス学