Exploration for novel anti-enterovirus compounds and identification of target host factors

• Project/Area Number: 16K08822
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Arita Minetaro 国立感染症研究所, ウイルス第二部, 主任研究官 (70356244)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 抗ウイルス薬 / ウイルス / 複製 / 宿主因子 / PI4KB / OSBP / エンテロウイルス / ポリオウイルス / ピコルナウイルス / 阻害剤 / アロステリック制御 / 作用機序 / 脂質 / ウィルス / 薬学

Outline of Final Research Achievements

We analyzed poliovirus mutants that showed partial resistance to inhibitors to host PI4KB/OSBP proteins, and found that the resistance mutation in viral 3A protein enhances the cleavage of viral 3AB protein by viral protease. We identified the target of previously uncharacterized anti-enterovirus compound MDL-860 as PI4KB, and discovered allosteric regulation of PI4KB via modification of cysteine residue at amino acid 646 by MDL-860. We isolated a poliovirus mutant that could show substantially complete resistance to PI4KB/OSBP inhibitors in vitro.

Academic Significance and Societal Importance of the Research Achievements

PI4KB/OSBP経路は、エンテロウイルスの複製に必要と考えられている宿主の経路であり、かつ低い細胞毒性を示す抗エンテロウイルス化合物の標的でもあるため、ウイルス複製における役割の解明が期待されています。今回の研究の中で、世界で初めてPI4KBのアロステリック制御機構を発見し、またPI4KB/OSBP阻害剤に耐性を示すウイルスの複製機構の一端の解明に成功しました。これらは、ウイルスの複製の本質およびウイルスの進化に関する学術的な重要性を持つ知見であるとともに、将来的には抗ウイルス治療におけるウイルスの耐性動態を制御出来る技術の開発にもつながることも期待されます。

Research Products

• [Int'l Joint Research] Universite Cote d’Azur/CNRS(フランス)
• [Int'l Joint Research] Bulgarian Academy of Sciences(Bulgaria)
• [Int'l Joint Research] University of Innsbruck(Austria)
• [Int'l Joint Research]
• [Int'l Joint Research] Dartmouth-Hitchcock Medical Center(米国)
• [Int'l Joint Research] Bulgarian Academy of Sciences(Bulgaria)
• [Int'l Joint Research] University of Innsbruck(Austria)
• [Journal Article] Poliovirus Evolution toward Independence from the Phosphatidylinositol‐4 Kinase III β/Oxysterol-Binding Protein Family I Pathway (2019)
  • Author(s): Minetaro Arita, and Joelle Bigay
  • Journal Title: ACS Infectious Dieases Volume: 印刷中 Issue: 6 Pages: 962-973
  • DOI: 10.1021/acsinfecdis.9b00038
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Allosteric regulation of phosphatidylinostol 4-kinase III beta by an antipicornavirus compound MDL-860 (2017)
  • Author(s): Arita M., Dobrikov G., Purstinger G., Galabov A.S.
  • Journal Title: ACS Infectious Diseases Volume: 3 Issue: 8 Pages: 585-594
  • DOI: 10.1021/acsinfecdis.7b00053
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Poliovirus Studies during the Endgame of the Polio Eradication Program (2017)
  • Author(s): Minetaro Arita
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 70 Issue: 1 Pages: 1-6
  • DOI: 10.7883/yoken.JJID.2016.356
  • NAID: 130005296392
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Antiviral update (2017)
  • Author(s): Minetaro Arita
  • Organizer: 20th Polio Research Committee Meeting
  • Int'l Joint Research
• [Presentation] 宿主因子を標的とする抗エンテロウイルス化合物の探索およびウイルス複製/宿主細胞への影響の解析 (2017)
  • Author(s): 有田 峰太郎
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台、東北大学川内北キャンパス
  • Invited
• [Presentation] 宿主因子を標的とするポリオウイルス複製阻害剤の探索 (2016)
  • Author(s): 有田 峰太郎
  • Organizer: 第89回日本生化学大会
  • Place of Presentation: 仙台、仙台国際センター
  • Invited