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Analysis of off-target activities of an anti-fungal drug Itraconazole

Research Project

Project/Area Number 17K15487
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Drug development chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

Ohgane Kenji  東京大学, 定量生命科学研究所, 助教 (30771092)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywordsイトラコナゾール / オフターゲット / NPC1 / ファーマコロジカルシャペロン / 光親和性標識 / itraconazole / ケミカルプローブ / ニーマンピック病C型 / シャペロン / ステロール / ケミカルバイオロジー / オフターゲット標的 / 医薬化学 / 構造活性相関
Outline of Final Research Achievements

We revealed that itraconazole, a widely used antifungal that targets ergosterol synthesis in fungi, serves as a pharmacological chaperone for an NPC1 mutant responsible for Niemann-Pick type C disease. Employing photo-crosslinking approach, we demonstrated direct interaction of itraconazole and the NPC1 mutant, which leads to stabilization of the folding-defective, unstable NPC1 mutant.

Academic Significance and Societal Importance of the Research Achievements

遺伝性難病の原因として、特定のタンパク質に変異が入り、そのタンパク質の三次元構造(フォールディング)に異常をきたす場合があります。そのようなフォールディング異常タンパク質は、細胞により不良品として認識されて分解されてしまいます。本研究では、そのようなフォールディング異常で起こりうる疾患の一つ、ニーマンピック病C型に関して、原因となるNPC1タンパク質変異体のフォールディング異常を修正する化合物の探索を行い、既存薬の中からいくつかの候補化合物を見出し、その作用機序の解析を行いました。ただちに薬となる訳ではありませんが、これらの化合物・知見は治療薬の開発に向けた研究の進展に寄与すると考えられます。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (26 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (3 results) Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 2 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] University of New South Wales(オーストラリア)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Evotec AG(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] Meharry Medical College(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate2020

    • Author(s)
      Hiromasa Yoshioka, Hudson W. Coates, Ngee Kiat Chua, Yuichi Hashimoto, Andrew J. Brown, Kenji Ohgane
    • Journal Title

      Proceedings of the National Academy of Sciences of the United States of America

      Volume: 117 Issue: 13 Pages: 7150-7158

    • DOI

      10.1073/pnas.1915923117

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Luciferase-based HMG-CoA reductase degradation assay for activity and selectivity profiling of oxy(lano)sterols2020

    • Author(s)
      Sagimori Ikuya、Yoshioka Hiromasa、Hashimoto Yuichi、Ohgane Kenji
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 28 Issue: 3 Pages: 115298-115298

    • DOI

      10.1016/j.bmc.2019.115298

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Application of protein knockdown strategy targeting β-sheet structure to multiple disease-associated polyglutamine proteins2020

    • Author(s)
      Yamashita Hiroko、Tomoshige Shusuke、Nomura Sayaka、Ohgane Kenji、Hashimoto Yuichi、Ishikawa Minoru
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 28 Issue: 1 Pages: 115175-115175

    • DOI

      10.1016/j.bmc.2019.115175

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiplexing fluorogenic esterase-based viability assay with luciferase assays2019

    • Author(s)
      Ohgane Kenji、Yoshioka Hiromasa、Hashimoto Yuichi
    • Journal Title

      MethodsX

      Volume: 6 Pages: 2013-2020

    • DOI

      10.1016/j.mex.2019.09.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton2019

    • Author(s)
      Nanjyo Shun、Ohgane Kenji、Yoshioka Hiromasa、Makishima Makoto、Hashimoto Yuichi、Noguchi- Yachide Tomomi
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 27 Issue: 10 Pages: 1952-1961

    • DOI

      10.1016/j.bmc.2019.03.042

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole2018

    • Author(s)
      Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 28 Issue: 4 Pages: 707-710

    • DOI

      10.1016/j.bmcl.2018.01.012

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Unexpected Emergence of Luciferase-Inhibitory Activity During Structural Development Study of Phenyloxadiazole-based Ppar Ligands2018

    • Author(s)
      Ryuta Shioi, Yosuke Toyota, Tomomi Noguchi-Yachide, Minoru Ishikawa, Takao Yamaguchi, Makoto Makishima, Yuichi Hashimoto, and Kenji Ohgane
    • Journal Title

      HETEROCYCLES

      Volume: 97 Issue: 2 Pages: 854-864

    • DOI

      10.3987/com-18-s(t)61

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Discovery of Small Molecules that Induce the Degradation of Huntingtin2017

    • Author(s)
      Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, and Minoru Ishikawa
    • Journal Title

      Angew. Chem. Int. Ed. Engl.

      Volume: 56 Issue: 38 Pages: 11530-11533

    • DOI

      10.1002/anie.201706529

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Reactivity of 7-Azanorbornenes in Bioorthogonal Inverse Electron-Demand Diels-Alder Reactions.2017

    • Author(s)
      Karaki, F.; Ohgane, K.; Imai, H.; Itoh, K.; Fujii, H.
    • Journal Title

      Eur. J. Org. Chem.

      Volume: 2017 Issue: 26 Pages: 3815-3829

    • DOI

      10.1002/ejoc.201700411

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein2017

    • Author(s)
      Hiromitsu Fukuda, Fumika Karaki, Kosuke Dodo, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto, Kenji Ohgane
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 27 Issue: 12 Pages: 2781-2787

    • DOI

      10.1016/j.bmcl.2017.04.062

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] コレステロール輸送膜タンパク質NPC1/NPC1L1を標的とした、フォールディング・局在異常を制御する小分子の探索2019

    • Author(s)
      大金賢司
    • Organizer
      第14回トランスポーター研究会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Squalene as a new feedback factor of squalene epoxidase stability2019

    • Author(s)
      Hiromasa Yoshioka, Ngee Kiat Chua, Hudson W. Coates, Yuichi Hashimoto, Andrew J. Brown, Kenji Ohgane
    • Organizer
      60th International Conference on the Bioscienceof Lipids (ICBL)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Chemical biology approach to understand small molecule-mediated degradation of HMG-CoA reductase2019

    • Author(s)
      Kenji Ohgane, Hiromasa Yoshioka, Ikuya Sagimori, Yuichi Hashimoto
    • Organizer
      60th International Conference on the Bioscienceof Lipids (ICBL)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 銀アセチリドの化学に基づく直接的アルキン濃縮精製法の開発2019

    • Author(s)
      大金 賢司, 淺沼三和子, 中尾周平, 境太希, どど孝介, 袖岡幹子
    • Organizer
      日本ケミカルバイオロジー学会第14回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] イトラコナゾールのNPC1に対するシャペロン作用に着目した構造活性相関研究2018

    • Author(s)
      安藤有輝,塩井隆太, 吉岡広大,谷内出友美, 石川稔, 橋本祐一,大金賢司
    • Organizer
      第36回メディシナルケミストリーシンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] ニーマンピック病C型に対する化学的アプローチ2018

    • Author(s)
      大金賢司
    • Organizer
      理研シンポジウム 第13回有機合成化学のフロンティア
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] identification of chaperone drugs for NPC through drug repurposing screening2018

    • Author(s)
      Kenji Ohgane
    • Organizer
      Michael, Marcia and Christa Parseghian Scientific Conference for Niemann-Pick Type C Research (Ara Parseghian Medical Research Fund at Notre Dame)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ItraconazoleのNPC1シャペロンとしての構造活性相関研究2018

    • Author(s)
      安藤有輝, 塩井隆太, 吉岡広大, 谷内出友美, 石川稔, 橋本祐一, 大金賢司
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ER downregulationの母核横断的な構造活性相関2018

    • Author(s)
      南條舜, 谷内出友美, 吉岡広大, 槇島誠, 石川稔, 橋本祐一, 大金賢司
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ドラッグリポジショニングによるニーマンピック病C型に対するシャペロンドラッグの探索2017

    • Author(s)
      大金賢司, 塩井隆太, 安藤有輝, 谷内出友美, 石川稔, どど孝介, 袖岡幹子, 橋本祐一
    • Organizer
      第35会メディシナルケミストリーシンポジウム
    • Related Report
      2017 Research-status Report
  • [Book] 膜タンパク質工学ハンドブック2020

    • Author(s)
      監修: 津本浩平、浜窪隆雄 (分担執筆者: 大金賢司 他130名)
    • Total Pages
      624
    • Publisher
      エヌ・ティー・エス出版
    • ISBN
      9784860435370
    • Related Report
      2019 Annual Research Report
  • [Remarks] コレステロール合成経路の新たな制御ポイント

    • URL

      http://www.iam.u-tokyo.ac.jp/wordpress/wp-content/uploads/2020/03/pressrelease_200310.pdf

    • Related Report
      2019 Annual Research Report
  • [Remarks] UTokyo FOCUS

    • URL

      https://www.u-tokyo.ac.jp/focus/en/articles/z0508_00082.html

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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