Exploration for novel anti-enterovirus compounds and identification of its host targets

• Project/Area Number: 25460579
• 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, その他部局等, 研究員 (70356244)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: エンテロウイルス / 抗ウイルス薬 / 宿主因子 / 複製 / PI4KB / OSBP / VCP/p97 / ウイルス / 膜輸送 / ポリオウイルス

Outline of Final Research Achievements

Idendified anti-enterovirus compounds were classified into direct-acting compounds to viral proteins, and PI4KB/OSBP inhibitors. PI4KB/OSBP pathway is required for formation of a virus replication complex by accumulating unesterified cholesterol on virus-induced membrane structure, rather than directly involved in viral RNA synthesis. These results suggested that evaluation of the effectiveness of the PI4KB/OSBP inhibitors is essential in development of anti-enterovirus drug targeting host factor activity.

Research Products

• [Int'l Joint Research] Frank J.M. van Kuppeveld/Utrecht University(オランダ)
• [Int'l Joint Research] Angel S. Galabov/Bulgarian Academy of Sciences(ブルガリア)
• [Journal Article] Mechanism of poliovirus resistance to host phosphatidylinositol-4 kinase III beta inhibitor (2016)
  • Author(s): Minetaro Arita
  • Journal Title: ACS Infectious Diseases Volume: 2 Issue: 2 Pages: 140-148
  • DOI: 10.1021/acsinfecdis.5b00122
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphatidylinositol 4-Kinase III Beta is the target of oxoglaucine and pachypodol (Ro 09-0179) for their anti-poliovirus activities, and locates at upstream of the target step of brefeldin A (2015)
  • Author(s): Minetaro Arita, Stefan Philipov, Angel S. Galabov
  • Journal Title: Microbiology and Immunology Volume: 未定 Issue: 6 Pages: 338-347
  • DOI: 10.1111/1348-0421.12261
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein (2015)
  • Author(s): Strating JR, van der Linden L, Albulescu L, Bigay J, Arita M, Delang L, Leyssen P, van der Schaar HM, Lanke KH, Thibaut HJ, Ulferts R, Drin G, Schlinck N, Wubbolts RW, Sever N, Head SA, Liu JO, Beachy PA, De Matteis MA, Shair MD, Olkkonen VM, Neyts J, van Kuppeveld FJ.
  • Journal Title: Cell reports Volume: 10 Issue: 4 Pages: 600-615
  • DOI: 10.1016/j.celrep.2014.12.054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phosphatidylinositol-4 kinase III beta and oxysterol-binding protein accumulate unesterified cholesterol on poliovirus-induced membrane structure (2014)
  • Author(s): Minetaro Arita
  • Journal Title: Microbiology and Immunology Volume: 58 Issue: 4 Pages: 239-256
  • DOI: 10.1111/1348-0421.12144
  • Peer Reviewed
• [Journal Article] 感染症の治療に向けて - ポリオ根絶計画におけるアカデミア創薬の試み (2014)
  • Author(s): 有田 峰太郎
  • Journal Title: 実験医学増刊号、研究成果を薬につなげるアカデミア創薬の戦略と実例 Volume: 32 Pages: 205-209
• [Journal Article] 抗エンテロウイルス化合物群の探索とそのウイルス感染阻害機構の解析 (2013)
  • Author(s): 有田 峰太郎
  • Journal Title: ウイルス Volume: 63 Pages: 93-102
  • NAID: 10031187710
• [Journal Article] 抗エンテロウイルス化合物群の探索研究 (2013)
  • Author(s): 有田 峰太郎
  • Journal Title: ファルマシア Volume: 49 Pages: 1095-1100
  • NAID: 110009995630
• [Presentation] PI4KBは、抗ピコルナウイルス化合物oxoglaucineおよびpachypodol (Ro 09-0179)の直接の標的である (2015)
  • Author(s): 有田 峰太郎
  • Organizer: 第25回抗ウイルス療法学会総会
  • Place of Presentation: 国立感染症研究所、東京
  • Year and Date: 2015-05-22
• [Presentation] PI4KB/OSBP 経路はポリオウイルス感染で誘導される膜構造にコレステロールを蓄積する (2014)
  • Author(s): 有田 峰太郎
  • Organizer: 第62回 日本ウイルス学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10
• [Presentation] フェノタイプスクリーニングの利用例 - 抗エンテロウイルス化合物群の同定と解析 (2014)
  • Author(s): 有田 峰太郎
  • Organizer: CBI学会研究講演会
  • Place of Presentation: 東京大学（山上会館）
  • Year and Date: 2014-09-02
  • Invited
• [Presentation] OSBPファミリーIはminor enviroxime様化合物の標的である (2013)
  • Author(s): 有田 峰太郎
  • Organizer: 第61回 日本ウイルス学会総会
  • Place of Presentation: 神戸