Development of Inhibitors for Influenza Endonuclease Activity

• Project/Area Number: 18K07138
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Chiba University
• Principal Investigator: Hoshino Tyuji 千葉大学, 大学院薬学研究院, 准教授 (90257220)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 抗ウイルス薬 / インフルエンザ / 医薬品設計 / 結晶構造解析 / 有機合成 / 計算機解析 / 阻害薬物 / インフルエンザウイルス / エンドヌクレアーゼ活性 / 計算機薬物設計 / 化合物合成 / X線結晶構造解析 / X線共結晶構造解析 / 阻害剤 / 薬物設計 / 阻害活性測定 / ポリメラーゼ

Outline of Final Research Achievements

An influenza inhibitor candidate was developed by targeting an endonuclease active site included in the RNA polymerase of influenza virus. Since the compounds identified by the compound screening commonly contained a skeleton called pyrogallol, the development was advanced on the compound with the pyrogallol skeleton. Based on the results of crystal structure analysis, several transformation structures were devised. The binding affinity between the compound and the active site was calculated as a binding score on a computer, and the compound structure to be synthesized was determined by referring to the calculated score. Among the synthesized compounds, a compound with a high inhibitory activity compound was identified.

Academic Significance and Societal Importance of the Research Achievements

インフルエンザ治療薬としては、オセルタミビル、ザミナビル、ペラミビルなどが知られている。これらの薬物は、ウイルスのノイラミニダーゼという酵素を標的としている。また緊急時のみの処方となるが、RNAポリメラーゼ活性を阻害するファビピラビルも認可されている。一般にウイルスは容易にアミノ酸変異が起こるために、薬の効かない薬剤耐性ウイルスが出現し、臨床で深刻な問題となる。ウイルスの薬剤耐性に対処するためには、複数の薬剤群を揃えて、最適な薬剤を選択できるようにすることが肝要であり、本研究は、将来的な抗ウイルス薬物治療の発展につながる。

Research Products

• [Journal Article] Analysis of Binding Modes of Antigen-Antibody Complexes by Molecular Mechanics Calculation (2021)
  • Author(s): Qu, L., Qiao, X., Qi, F., Nishida, N., Hoshino, T.
  • Journal Title: J. Chem. Inform. Model. Volume: 61
  • Peer Reviewed
• [Journal Article] Electrostatic Potentials around the Proteins Preferably Crystallized by Ammonium Sulfate (2020)
  • Author(s): Guo Yan、Qu Liang、Nishida Noritaka、Hoshino Tyuji
  • Journal Title: Crystal Growth & Design Volume: 21 Issue: 1 Pages: 297-305
  • DOI: 10.1021/acs.cgd.0c01136
  • Peer Reviewed
• [Journal Article] Computational Study on the Assembly of Amyloid β-Peptides in the Hydrophobic Environment (2019)
  • Author(s): Qu Liang、Fudo Satoshi、Matsuzaki Katsumi、Hoshino Tyuji
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 67 Issue: 9 Pages: 959-965
  • DOI: 10.1248/cpb.c19-00171
  • NAID: 130007699659
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2019-09-01
• [Journal Article] Anisotropic Distribution of Ammonium Sulfate Ions in Protein Crystallization (2019)
  • Author(s): Kitahara Mariko、Fudo Satoshi、Yoneda Tomoki、Nukaga Michiyoshi、Hoshino Tyuji
  • Journal Title: Crystal Growth & Design Volume: 19 Issue: 11 Pages: 6004-6010
  • DOI: 10.1021/acs.cgd.9b00256
• [Journal Article] Simulation Time Required for Diminishing the Initial Conformational Deviations among Protein Crystal Structures (2018)
  • Author(s): Qi Fei、Yoneda Tomoki、Neya Saburo、Hoshino Tyuji
  • Journal Title: The Journal of Physical Chemistry B Volume: 122 Issue: 36 Pages: 8503-8515
  • DOI: 10.1021/acs.jpcb.8b04800
• [Presentation] インフルエンザのエンドヌクレアーゼ活性を阻害する化合物の合成と結合構造解析 (2019)
  • Author(s): 齋藤 聡、米田 友貴、額賀 路嘉、山本 典生、星野 忠次
  • Organizer: 日本薬学会第139年会
• [Remarks] 千葉大学大学院薬学研究院 薬品物理化学研究室
  • URL: http://www.p.chiba-u.jp/lab/bukka/index.html
• [Remarks] 千葉大学大学院薬学研究院薬品物理化学研究室
  • URL: http://www.p.chiba-u.jp/lab/bukka/index.html