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Identification and development of inhibitors for reactive sulfur-generating enzymes by utilizing fluorescent probes

Publicly Offered Research

Project AreaFrontier research of chemical communications
Project/Area Number 18H04609
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

花岡 健二郎  東京大学, 大学院薬学系研究科(薬学部), 准教授 (70451854)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords薬学 / 分析科学 / 生体分子 / 分子認識 / 有機化学 / 蛍光プローブ / 酵素阻害剤 / 阻害剤スクリーニング
Outline of Annual Research Achievements

本研究において、活性イオウ分子産生酵素の選択的阻害剤の探索、構造最適化を通して、活性イオウ分子の機能解明に有用な新たな阻害剤の開発を行うことを目的としている。特に、これまでに開発に成功している、活性イオウ分子を選択的に検出する蛍光プローブ群を用いることで、多数の化合物ライブラリーから阻害剤候補となるリード化合物を効率的かつ独自のアプローチによってスクリーニングを行う。平成30年度には、酵素反応によって産生されるH2Sをこれまで研究代表者らが開発したH2S検出蛍光プローブを用いて検出することでハイスループットスクリーニングを行い、CSE(cystathionine γ-lyase)に対して選択的かつ11 μMのIC50値を示す新たな阻害剤を見出すことに成功している。本年度は、新たに見出した阻害剤のCSEに対する阻害形式をSPR測定や共結晶解析、蛍光スペクトル測定などによって詳細に明らかにすると共に、これら阻害剤の構造最適化および生細胞への応用にも成功した。特に、開発したCSE阻害剤が生細胞に対しても有用であることの検討はその有用性を示す上で非常に重要であり、CSE過剰発現細胞においてCSE阻害活性を示すこと、およびLC-MS/MS解析によって開発したCSE阻害剤が細胞内のアミノ酸代謝物を変化させることを明らかにした。さらに、これまでに研究代表者らによって開発されているH2Sやsulfane sulfurを検出する蛍光プローブ群や3MST(3-mercaptopyrvate sulfurtransferase)の選択的阻害剤を国内外の研究者らに広く供与し共同研究を行った。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (47 results)

All 2020 2019 2018 Other

All Int'l Joint Research (4 results) Journal Article (16 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 6 results) Presentation (21 results) (of which Int'l Joint Research: 5 results,  Invited: 11 results) Book (4 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] Ben-Gurion University(イスラエル)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Harvard Medical School(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Kent State University/Beckman Research Institute(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] German Cancer Research Center (DKFZ)(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Rational Design of A Near-infrared Fluorescence Probe for Ca2+ Based on Phosphorus-substituted Rhodamines Utilizing Photoinduced Electron Transfer2020

    • Author(s)
      Shodai Takahashi, Kenjiro Hanaoka, Yohei Okubo, Honami Echizen, Takayuki Ikeno, Toru Komatsu, Tasuku Ueno, Kenzo Hirose, Masamitsu Iino, Tetsuo Nagano, Yasuteru Urano
    • Journal Title

      Chem. Asian J.

      Volume: 15 Issue: 4 Pages: 524-530

    • DOI

      10.1002/asia.201901689

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-inducible factor-1 alpha maintains mouse articular cartilage through suppression of NF-κB signaling2020

    • Author(s)
      Okada Keita、Mori Daisuke、Makii Yuma、Nakamoto Hideki、Murahashi Yasutaka、Yano Fumiko、Chang Song Ho、Taniguchi Yuki、Kobayashi Hiroshi、Semba Hiroaki、Takeda Norihiko、Piao Wen、Hanaoka Kenjiro、Nagano Tetsuo、Tanaka Sakae、Saito Taku
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 5425-5425

    • DOI

      10.1038/s41598-020-62463-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Fluorescent Probe for Rapid, High-Contrast Visualization of Folate-Receptor-Expressing Tumors in Vivo2020

    • Author(s)
      Koji Numasawa, Kenjiro Hanaoka, Naoko Saito, Yoshifumi Yamaguchi, Takayuki Ikeno, Honami Echizen, Masahiro Yasunaga, Toru Komatsu, Tasuku Ueno, Masayuki Miura, Tetsuo Nagano, Yasuteru Urano
    • Journal Title

      Angew. Chem. Int. Ed.

      Volume: 59 Issue: 15 Pages: 6015-6020

    • DOI

      10.1002/anie.201914826

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of Novel Dark Quenchers and Their Application to Imaging Probes2019

    • Author(s)
      Kenjiro Hanaoka
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 139 Issue: 2 Pages: 277-283

    • DOI

      10.1248/yakushi.18-00174-3

    • NAID

      130007587179

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2019-02-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design of Photostable, Activatable Near‐Infrared Photoacoustic Probes Using Tautomeric Benziphthalocyanine as a Platform2019

    • Author(s)
      Naoyuki Toriumi, Norihito Asano, Takayuki Ikeno, Atsuya Muranaka, Kenjiro Hanaoka, Yasuteru Urano, Masanobu Uchiyama
    • Journal Title

      Angew. Chem. Int. Ed.

      Volume: 58 Issue: 23 Pages: 7788-7791

    • DOI

      10.1002/anie.201903303

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design and Synthesis of an Activatable Photoacoustic Probe for Hypochlorous Acid2019

    • Author(s)
      Ikeno Takayuki、Hanaoka Kenjiro、Iwaki Shimpei、Myochin Takuya、Murayama Yoshiaki、Ohde Hisashi、Komatsu Toru、Ueno Tasuku、Nagano Tetsuo、Urano Yasuteru
    • Journal Title

      Analytical Chemistry

      Volume: 91 Issue: 14 Pages: 9086-9092

    • DOI

      10.1021/acs.analchem.9b01529

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design strategy for germanium-rhodamine based pH-activatable near-infrared fluorescence probes suitable for biological applications2019

    • Author(s)
      Yuichiro Koide, Ryosuke Kojima, Kenjiro Hanaoka, Koji Numasawa, Toru Komatsu, Tetsuo Nagano, Hisataka Kobayashi, Yasuteru Urano
    • Journal Title

      Commun. Chem.

      Volume: 2 Issue: 1 Pages: 94-94

    • DOI

      10.1038/s42004-019-0194-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Separation-Based Enzymomics Assay for the Discovery of Altered Peptide-Metabolizing Enzymatic Activities in Biosamples2019

    • Author(s)
      Ichihashi Yuki、Komatsu Toru、Kyo Etsu、Matsuzaki Hiroyuki、Hata Keisuke、Watanabe Toshiaki、Ueno Tasuku、Hanaoka Kenjiro、Urano Yasuteru
    • Journal Title

      Analytical Chemistry

      Volume: 91 Issue: 18 Pages: 11497-11501

    • DOI

      10.1021/acs.analchem.9b03016

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of ratiometric carbohydrate sensor based on boron dipyrromethene (BODIPY) scaffold2019

    • Author(s)
      Cheruthu Nusaiba Madappuram、Komatsu Toru、Ueno Tasuku、Hanaoka Kenjiro、Urano Yasuteru
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 29 Issue: 22 Pages: 126684-126684

    • DOI

      10.1016/j.bmcl.2019.126684

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolic-Pathway-Oriented Screening Targeting S-Adenosyl-l-methionine Reveals the Epigenetic Remodeling Activities of Naturally Occurring Catechols2019

    • Author(s)
      Ogihara Shusuke、Komatsu Toru、Itoh Yukihiro、Miyake Yuka、Suzuki Takayoshi、Yanagi Kouichi、Kimura Yusuke、Ueno Tasuku、Hanaoka Kenjiro、Kojima Hirotatsu、Okabe Takayoshi、Nagano Tetsuo、Urano Yasuteru
    • Journal Title

      Journal of the American Chemical Society

      Volume: 142 Issue: 1 Pages: 21-26

    • DOI

      10.1021/jacs.9b08698

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production2018

    • Author(s)
      Ezerina D, Takano Y, Hanaoka K, Urano Y, Dick TP
    • Journal Title

      Cell Chem Biol.

      Volume: 25 Issue: 4 Pages: 447-459

    • DOI

      10.1016/j.chembiol.2018.01.011

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A protein-coupled fluorescent probe for organelle-specific imaging of Na+2018

    • Author(s)
      Ryo Taguchi, Takuya Terai, Tasuku Ueno, Toru Komatsu, Kenjiro Hanaoka, and Yasuteru Urano
    • Journal Title

      Sensor Actuat. B-Chem.

      Volume: 265 Pages: 575-581

    • DOI

      10.1016/j.snb.2018.03.090

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of a Series of Practical Fluorescent Chemical Tools to Measure pH Values in Living Samples2018

    • Author(s)
      Takahashi Shodai、Kagami Yu、Hanaoka Kenjiro、Terai Takuya、Komatsu Toru、Ueno Tasuku、Uchiyama Masanobu、Koyama-Honda Ikuko、Mizushima Noboru、Taguchi Tomohiko、Arai Hiroyuki、Nagano Tetsuo、Urano Yasuteru
    • Journal Title

      Journal of the American Chemical Society

      Volume: 140 Issue: 18 Pages: 5925

    • DOI

      10.1021/jacs.8b00277

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of unsymmetrical Si-rhodamine fluorophores and application to a far-red to near-infrared fluorescence probe for hypoxia2018

    • Author(s)
      Hanaoka Kenjiro、Kagami Yu、Piao Wen、Myochin Takuya、Numasawa Koji、Kuriki Yugo、Ikeno Takayuki、Ueno Tasuku、Komatsu Toru、Terai Takuya、Nagano Tetsuo、Urano Yasuteru
    • Journal Title

      Chemical Communications

      Volume: 54 Issue: 50 Pages: 6939-6942

    • DOI

      10.1039/c8cc02451k

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Red-Shifted Fluorogenic Substrate for Detection of lacZ-Positive Cells in Living Tissue with Single-Cell Resolution2018

    • Author(s)
      Ito Hiroki、Kawamata Yu、Kamiya Mako、Tsuda-Sakurai Kayoko、Tanaka Shinji、Ueno Tasuku、Komatsu Toru、Hanaoka Kenjiro、Okabe Shigeo、Miura Masayuki、Urano Yasuteru
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 57 Issue: 48 Pages: 15702-15706

    • DOI

      10.1002/anie.201808670

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rapid detection of metastatic lymph nodes of colorectal cancer with a gamma-glutamyl transpeptidase-activatable fluorescence probe2018

    • Author(s)
      Kubo Hidemasa、Hanaoka Kenjiro、Kuriki Yugo、Komatsu Toru、Ueno Tasuku、Kojima Ryosuke、Kamiya Mako、Murayama Yasutoshi、Otsuji Eigo、Urano Yasuteru
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 17781-6942

    • DOI

      10.1038/s41598-018-36062-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Development of fluorescence probes for H2S and sulfane sulfur and their application to the inhibitor screening2019

    • Author(s)
      Kenjiro Hanaoka
    • Organizer
      1st International Conference on Persulfide and Sulfur Metabolism in Biology and Medicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Development of a Fluorescence Probe for H2S and its Application to Inhibitor Screening for H2S-Producing Enzymes2019

    • Author(s)
      Kenjiro Hanaoka, Kiyoshi Sasakura, Tetsuo Nagano, Yasuteru Urano
    • Organizer
      The 15th International Symposium on Applied Bioinorganic Chemistry (ISABC15)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of a fluorescence probe for H2S and its application to inhibitor screening for H2S-producing enzymes2019

    • Author(s)
      Kenjiro Hanaoka
    • Organizer
      The Joint Symposium of “10th Korea-Japan Chemical Biology Symposium” and “30th Meeting for New Drug Discovery”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 活性イオウ分子産生酵素 cystathionine β-synthase (CBS) に対する選択的阻害剤の開発2019

    • Author(s)
      越膳ほなみ、花岡健二郎、土屋幸弘、渡邊泰男、岡部隆義、浦野泰照
    • 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] 活性イオウ分子sulfane sulfurを可逆的に検出する蛍光プローブの開発2019

    • Author(s)
      花岡健二郎、高野陽子、島本一史、浦野泰照
    • Organizer
      新学術領域研究「化学コミュニケーションのフロンティア」第5回公開シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 活性イオウ分子産生酵素cystathionine γ-lyase (CSE)に対する選択的阻害剤の開発2019

    • Author(s)
      花岡健二郎
    • Organizer
      新学術領域研究「化学コミュニケーションのフロンティア」第6回公開シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規蛍光団の創製を基盤とした蛍光プローブの開発2019

    • Author(s)
      花岡 健二郎
    • Organizer
      新学術領域「化学コミュニケーションのフロンティア」第2回 若手シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 生体内の低酸素・pHを可視化する蛍光プローブの開発2019

    • Author(s)
      花岡 健二郎
    • Organizer
      第44回日本微小循環学会総会 シンポジウム1「微小環境をみる,はかる,感知する」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 分子レジデンスを制御した近赤外蛍光葉酸受容体検出蛍光プローブの開発2019

    • Author(s)
      花岡 健二郎
    • Organizer
      日本化学会 第99春季年会 (2019) 分子のレジデンスを考えるー新しい機能分子設計の鍵としてー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Development and application of fluorescence probes for detecting reactive sulfur species (RSS)2019

    • Author(s)
      花岡 健二郎
    • Organizer
      第92回日本薬理学会年会 107 「硫化水素をはじめとした生理活性イオウ研究の新展開」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 生体内低酸素環境を可視化する蛍光プローブの開発2019

    • Author(s)
      花岡 健二郎
    • Organizer
      日本薬学会 第139年会 一般シンポジウム S57 がん微小環境の理解とその克服に向けた薬学的アプローチ ~HIF-1αの理解と制御に向けて~
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Cystathionine β-synthase(CBS)に対する選択的 阻害剤の開発2019

    • Author(s)
      越膳 ほなみ
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Development of fluorescent probes for reactive sulfur species and their applications2018

    • Author(s)
      Kenjiro Hanaoka
    • Organizer
      5th World Congress on Hydrogen Sulfide in Biology & Medicine
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Development of a Series of Fluorescence Probes to Measure pH Values in Living Samples2018

    • Author(s)
      Kenjiro Hanaoka
    • Organizer
      7th Annual Conference of International Chemical Biology Society
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 活性イオウ分子を検出する蛍光プローブの開発と応用2018

    • Author(s)
      花岡 健二郎
    • Organizer
      第71回日本酸化ストレス学会・第18回日本NO学会 合同学術集会 合同シンポジウム「活性イオウ分子の生体分析と機能・病態解明の新世代研究」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 活性イオウ分子を検出する蛍光プローブの開発と阻害剤探索への応用2018

    • Author(s)
      花岡 健二郎
    • Organizer
      第91回日本生化学会大会 1S06p 「活性硫黄種の新展開ー硫化水素から過硫化物までー」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 新規蛍光団の創製を基盤とした蛍光プローブの開発2018

    • Author(s)
      花岡 健二郎
    • Organizer
      Chemical Probe (生命現象探索分子) 第一回合同合宿セミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] シッフ塩基形成を利用した活性イオウ分子産生酵素阻害剤の開発2018

    • Author(s)
      越膳 ほなみ
    • Organizer
      第71回酸化ストレス学会、第18回NO学会合同学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] シッフ塩基形成を利用した活性イオウ分子産生酵素阻害剤の開発2018

    • Author(s)
      越膳 ほなみ
    • Organizer
      日本ケミカルバイオロジー学会第13年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性イオウ分子産生酵素阻害剤の開発2018

    • Author(s)
      越膳 ほなみ
    • Organizer
      第16回次世代を担う若手のためのフィジカルファーマフォーラム(PPF2018)
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性イオウ分子産生酵素の選択的阻害剤の開発2018

    • Author(s)
      越膳 ほなみ
    • Organizer
      第12回バイオ関連化学シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Book] 日本薬理学雑誌, Vol.154, No.32019

    • Author(s)
      越膳ほなみ, 花岡健二郎
    • Publisher
      日本薬理学会
    • Related Report
      2019 Annual Research Report
  • [Book] B&I バイオサイエンスとインダストリー Vol.77, No.12019

    • Author(s)
      花岡 健二郎
    • Publisher
      (一般)バイオインダストリー協会
    • Related Report
      2018 Annual Research Report
  • [Book] 生化学, Vol.90, No.32018

    • Author(s)
      越膳 ほなみ,花岡 健二郎
    • Publisher
      日本生化学会
    • Related Report
      2018 Annual Research Report
  • [Book] 化学,November, Vol.732018

    • Author(s)
      花岡 健二郎
    • Publisher
      化学同人
    • Related Report
      2018 Annual Research Report
  • [Remarks] 東京大学 大学院薬学系研究科 薬品代謝化学教室

    • URL

      http://www.f.u-tokyo.ac.jp/~taisha/

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規無蛍光性ローダミン類2019

    • Inventor(s)
      花岡 健二郎、浦野 泰照、池野 喬之
    • Industrial Property Rights Holder
      国立大学法人 東京大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2018-04-23   Modified: 2021-01-27  

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