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Analysis of cellular machinery using PPI-inducing small molecules

Research Project

Project/Area Number 19H02839
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionNagoya University

Principal Investigator

KITA Masaki  名古屋大学, 生命農学研究科, 教授 (30335012)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsタンパク質間相互作用 / 天然物リガンド / アクチン / 標的分子同定 / 微小管阻害剤
Outline of Research at the Start

細胞骨格タンパク質アクチンに作用する天然物リガンドに注目して,創薬標的となる新たなPPI機能作用点の特定および関連する運動マシナリーの解明を目指す.細胞形態の観察や機能性分子プローブを用いたアフィニティー精製により,多様な天然物リガンドの第2の標的分子を同定し,三元複合体の構造や相互作用を解明する.プローブの細胞内動態やin vitro構築系でのダイナミクスへの影響を精査し,生物活性発現メカニズムを明らかにする.

Outline of Final Research Achievements

We focused on the natural ligands that interact with actin, and aimed to identify new protein-protein interaction (PPI) functional points that could become the targets for drug discovery, and to elucidate the moving machinery associated with the cytoskeleton. We synthesized structurally-simplified actin-binding derivatives of the antitumor natural product aprilonin A (ApA), which induces unique PPI between actin and tubulin to inhibit microtubule dynamics. Using this compounds, we successfully affinity-purified cytoskeletal actin from cell lysate. In addition, molecular docking simulation and molecular dynamics studies succeeded in constructing a possible model of the actin-ApA-tubulin ternary complex in which the C7 TMSer ester interacted with tubulin, which is important for the potent cytotoxicity of ApA.

Academic Significance and Societal Importance of the Research Achievements

PPIは生命現象を担うシグナル伝達系を調節し、重要な生理的効果を誘導する。近年,PPIを安定化もしくは阻害する化合物が多数見いだされ、疾患研究ツールや医薬リードとしても注目されている。本研究では動的で不安定な細胞骨格タンパク質を標的とする天然物に注目し、これまで未解明だった標的分子の同定、複合体の構造解析、および活性発現機構の解明に挑戦した点で学術的に高い意義があると考えられる。また、本研究で得られた成果は、副作用を低減した新たな医薬の創出や、複合的に機能する新たな薬理学ツールの開発といった学際的・分野融合的な研究へと展開できると期待されることから、社会的意義も高い成果と言える。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (46 results)

All 2022 2021 2020 2019 Other

All Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 10 results,  Open Access: 4 results) Presentation (29 results) (of which Int'l Joint Research: 12 results,  Invited: 11 results) Book (1 results) Remarks (3 results)

  • [Journal Article] Flavokawains, Plant-derived Chalcones, Inhibit Differentiation of Murine Pre-adipocytes2022

    • Author(s)
      Hanif Novriyandi、Iswantini Dyah、Hioki Yusuke、Murni Anggia、Kita Masaki、Tanaka Junichi
    • Journal Title

      Chemistry Letters

      Volume: 51 Issue: 1 Pages: 54-57

    • DOI

      10.1246/cl.210615

    • NAID

      130008137579

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Eumitrins F-H: three new xanthone dimers from the lichen <i>Usnea baileyi</i> and their biological activities2022

    • Author(s)
      Nguyen Van-Kieu、Nguyen-Si Hoai-Vu、Devi Asshaima Paramita、Poonsukkho Pakarapon、Sangvichien Ek、Tran Thanh-Nha、Yusuke Hioki、Mitsunaga Tohru、Chavasiri Warinthorn
    • Journal Title

      Natural Product Research

      Volume: 無し Issue: 9 Pages: 1-11

    • DOI

      10.1080/14786419.2021.2023143

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 6‐Paradol Acts as a Potential Anti‐obesity Vanilloid from Grains of Paradise2021

    • Author(s)
      Hattori Hiroyuki、Mori Takashi、Shibata Takahiro、Kita Masaki、Mitsunaga Tohru
    • Journal Title

      Molecular Nutrition &amp; Food Research

      Volume: 65 Issue: 16 Pages: 2100185-2100185

    • DOI

      10.1002/mnfr.202100185

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The C29-C34 parts of antitumor macrolide aplyronine A serve as versatile actin-affinity tags2021

    • Author(s)
      Utomo Didik Huswo、Fujieda Akari、Tanaka Kentaro、Takahashi Momoko、Futaki Kentaro、Tanabe Kenta、Kigoshi Hideo、Kita Masaki
    • Journal Title

      Chemical Communications

      Volume: 57 Issue: 81 Pages: 10540-10543

    • DOI

      10.1039/d1cc04259a

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] N,N-Dimethylaminopyrene as a fluorescent affinity mass tag for ligand-binding mode analysis2020

    • Author(s)
      Arai Atsushi、Watanabe Rei、Hattori Atsunori、Iio Keita、Hu Yaping、Yoneda Kozo、Kigoshi Hideo、Kita Masaki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 7311-7311

    • DOI

      10.1038/s41598-020-64321-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Isolation and structure?activity relationship studies of jacaranones: Anti-inflammatory quinoids from the Cuban endemic plant Jacaranda arborea (Bignoniaceae)2020

    • Author(s)
      Hirukawa Minako、Zhang Menghua、Echenique?Diaz Lazaro M.、Mizota Koji、Ohdachi Satoshi D.、Begu??Quiala Gerardo、Delgado?Laba?ino Jorge L.、G?mez?D?ez Jorgelino、Alvarez?Lemus Jos?、Machado Leandro Galano、N??ez Miguel Su?rez、Shibata Takahiro、Kigoshi Hideo、Kita Masaki
    • Journal Title

      Tetrahedron Letters

      Volume: 61 Issue: 26 Pages: 152005-152005

    • DOI

      10.1016/j.tetlet.2020.152005

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Acyl-CoA dehydrogenase long chain (ACADL) is a target protein of stylissatin A, an anti-inflammatory cyclic heptapeptide2020

    • Author(s)
      Zhang Menghua、Sunaba Taiki、Sun Yiting、Shibata Takahiro、Sasaki Kazunori、Isoda Hiroko、Kigoshi Hideo、Kita Masaki
    • Journal Title

      The Journal of Antibiotics

      Volume: 73 Issue: 8 Pages: 589-592

    • DOI

      10.1038/s41429-020-0322-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 哺乳類由来の神経毒の化学生物学研究2020

    • Author(s)
      北将樹
    • Journal Title

      化学工業

      Volume: 71 Pages: 73-78

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Anti-inflammatory marine cyclic peptide stylissatin A and its derivatives inhibit differentiation of murine preadipocytes2019

    • Author(s)
      Zhang Menghua、Sunaba Taiki、Sun Yiting、Sasaki Kazunori、Isoda Hiroko、Kigoshi Hideo、Kita Masaki
    • Journal Title

      Chemical Communications

      Volume: 55 Issue: 38 Pages: 5471-5474

    • DOI

      10.1039/c9cc02517k

    • NAID

      120006725321

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein?Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1?C9 Macrolactone Part and the C24?C34 Side Chain2019

    • Author(s)
      Futaki Kentaro、Takahashi Momoko、Tanabe Kenta、Fujieda Akari、Kigoshi Hideo、Kita Masaki
    • Journal Title

      ACS Omega

      Volume: 4 Issue: 5 Pages: 8598-8613

    • DOI

      10.1021/acsomega.9b01099

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Post K-Pg diversification of the mammalian order Eulipotyphla as suggested by phylogenomic analyses of ultra-conserved elements2019

    • Author(s)
      Sato Jun J.、Bradford Tessa M.、Armstrong Kyle N.、Donnellan Stephen C.、Echenique-Diaz Lazaro M.、Begu?-Quiala Gerardo、G?mez-D?ez Jorgelino、Yamaguchi Nobuyuki、Nguyen Son Truong、Kita Masaki、Ohdachi Satoshi D.
    • Journal Title

      Molecular Phylogenetics and Evolution

      Volume: 141 Pages: 106605-106605

    • DOI

      10.1016/j.ympev.2019.106605

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MyPR: 異分野融合型の天然物化学者を志す2019

    • Author(s)
      北将樹
    • Journal Title

      有機合成化学協会誌

      Volume: 77 Pages: 371-373

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Journal Article] 生理活性蛍光リガンドとLA-LDI MS ~標的生体分子の結合位置解析法の開発~2019

    • Author(s)
      北将樹
    • Journal Title

      生命化学研究レター

      Volume: 59 Pages: 7-11

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Presentation] アメフラシ由来新規aplaminone誘導体の発見と分子ネットワーク解析によるその起源の解明.2022

    • Author(s)
      日置裕介、栩野安友花、佐藤達也、岩尾豊紀、河村篤、北将樹
    • Organizer
      日本化学会第102春季年会, 大阪(オンライン)
    • Related Report
      2021 Annual Research Report
  • [Presentation] アクチン作用性海洋天然物を基盤とした新規PPI誘導分子の開発.2022

    • Author(s)
      田中健太郎、Utomo Didik Huswo、藤枝あかり、北将樹
    • Organizer
      日本化学会第102春季年会, 大阪(オンライン)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Structural Study of Actin-Aplyronine A-Tubulin Heterotrimeric Complex and Development of Actin-affinity Tags.2022

    • Author(s)
      Didik Huswo Utomo, Akari Fujieda, Atsunori Oshima, Akihiro Narita, Momoko Takahashi, Hideo Kigoshi, Masaki Kita
    • Organizer
      日本化学会第102春季年会, 大阪(オンライン)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Natural Product Prospect for Human Health.2021

    • Author(s)
      M. Kita
    • Organizer
      79th Airlangga Webinar Conference Series, Airlangga University, Indonesia (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Marine Natural Product Prospect for Human Health.2021

    • Author(s)
      M. Kita
    • Organizer
      The 5th International Conference of Medical and Health Sciences (ICMHS 5), Universitas Muhammadiyah Yogyakarta, Indonesia (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Target identification and binding mode analysis of bioactive natural products.2021

    • Author(s)
      M. Kita
    • Organizer
      A3フォーサイト事業取りまとめシンポジウム, TKPガーデンシティ仙台
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chemical Biology and Ecology Studies on Aplyronine A, A PPI-inducing Antitumor Macrolide from Sea Hare.2021

    • Author(s)
      M. Kita, D. H. Utomo, M. Morita, and H. Kigoshi
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM2021), Hawaii, USA (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Elucidation of the Origins of Marine Natural Products: Investigation of Aqueous Chemical Constituents of the Sea Hare Aplysia kurodai.2021

    • Author(s)
      Yusuke Hioki, Syarfina Az Zahra, Masaki Kita
    • Organizer
      The International Summer Course on Marine Natural Products (ISCMNP2021), Bogor Agricultural (IPB) University Bogor, Indonesia (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Revealing Binding Position of Aplyronine A as a Protein-Protein Interaction Inducer.2021

    • Author(s)
      Didik Huswo Utomo, Akari Fujieda, Hideo Kigoshi, Masaki Kita
    • Organizer
      The International Summer Course on Marine Natural Products (ISCMNP2021), Bogor Agricultural (IPB) University, Indonesia (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アクチンアフィニティータグの開発を志向したアプリロニンA側鎖類縁体の合成と機能評価.2021

    • Author(s)
      Didik Husuo Utomo, 藤枝あかり, 田中健太郎, 髙橋桃子, 二木健太郎, 田邉健太, 木越英夫, 北将樹
    • Organizer
      第63回天然有機化合物討論会、大阪(オンライン)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Anti-inflammation and adipogenesis inhibition functions of stylissatin A: Structure-activity relationship, target identification, and mode of action studies.2021

    • Author(s)
      Masaki Kita, Menghua Zhang, Taiki Sunaba, Yiting Sun, Takahiro Shibata, Kazunori Sasaki, Hiroko Isoda, and Hideo Kigoshi
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM2021) Hawaii, USA(オンライン)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Revealing Binding Position of Aplyronine A as A Protein-Protein Interaction Inducer.2021

    • Author(s)
      Didik H. Utomo, Maho Morita, Hideo Kigoshi, and Masaki Kita
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM2021) Hawaii, USA(オンライン)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the origins of marine natural products: Investigation of aqueous chemical constituents of the sea hare Aplysia kurodai.2021

    • Author(s)
      Yusuke Hioki, Atsushi Kawamura, and Masaki Kita
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM2021) Hawaii, USA(オンライン)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Target Proteins and Mode of Actions of Bioactive Marine Natural Products.2021

    • Author(s)
      M. Kita
    • Organizer
      The International Summer Course on Marine Natural Products (ISCMNP2021) Lecture 1, Bogor Agricultural University, Indonesia (on-line)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Target identification and binding mode analysis of bioactive marine natural products.2021

    • Author(s)
      M. Kita
    • Organizer
      理研CSRSランチョンセミナー, 理研環境資源科学研究センター(オンライン)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] キューバ産植物由来抗炎症物質jacaranoneの構造活性相関および標的分子同定2021

    • Author(s)
      蛭川美奈子,柴田貴広, 森田真布,北将樹
    • Organizer
      日本農芸化学会2021年度大会(口頭発表)
    • Related Report
      2020 Annual Research Report
  • [Presentation] ケミカルプローブを用いたstylissatin Aの標的タンパク質の解明2021

    • Author(s)
      神谷佳佑、Yiting Sun、張夢華、柴田貴広、森田真布、北将樹
    • Organizer
      日本化学会第101春季年会(口頭発表)
    • Related Report
      2020 Annual Research Report
  • [Presentation] Revealing Binding Position of Aplyronine A as a Protein-Protein Interaction Inducer2021

    • Author(s)
      Didik H. Utomo, Akari Fujieda, Maho Morita, Hideo Kigoshi, and Masaki Kita
    • Organizer
      日本化学会第101春季年会(口頭発表)
    • Related Report
      2020 Annual Research Report
  • [Presentation] キューバ産植物由来の抗炎症物質jacaranoneに関する研究2020

    • Author(s)
      蛭川美奈子、Lazaro M. Echenique-Diaz、溝田浩二、大舘智志、Gerardo Begue-Quiala、Jorge L. Delgado-Labanino、Jorgelino Gamez-Diez、柴田貴広、森田真布、北将樹
    • Organizer
      第62回天然有機化合物討論会(ポスター発表)
    • Related Report
      2020 Annual Research Report
  • [Presentation] タンパク質間相互作用を誘導する天然物の新展開2020

    • Author(s)
      北将樹
    • Organizer
      第100回日本化学会春季年会・中長期シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] リガンド解離型ピレンプローブを用いたリガンド結合様式の解析2020

    • Author(s)
      荒井厚志, 小幡紘平, 服部篤紀, 渡邊礼, 胡亜萍, 飯尾啓太, 米田耕三, 木越英夫, 北将樹
    • Organizer
      日本化学会第100春季年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Stylissatin Aの抗炎症および抗肥満活性の作用機序の解明2020

    • Author(s)
      張夢華, 砂場大輝, Yiting Sun, 柴田貴広, 佐々木一憲, 礒田博子, 木越英夫, 北将樹
    • Organizer
      日本化学会第100春季年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 食虫動物トガリネズミ由来の麻痺性神経毒ペプチドの構造と生物活性2020

    • Author(s)
      森田真布, 武仲敏子, 別所学, Maturana D. Andres, 木越英夫, 大舘智志, 上村大輔, 北将樹
    • Organizer
      日本農芸化学会2020年度大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 生理活性蛍光リガンドを用いた標的分子の結合様式解析2019

    • Author(s)
      北将樹
    • Organizer
      理研シンポジウム・第14回有機合成化学のフロンティア
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Bioorganic Studies on the Key Natural Products from Venomous Mammals and Marine Invertebrates.2019

    • Author(s)
      Kita, M.
    • Organizer
      8th International Conference of the Indonesian Chemical Society (ICICS 2019)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 切れ味の良い分子を自然界にもとめて2019

    • Author(s)
      北将樹
    • Organizer
      第3回函館セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 哺乳類由来の神経毒の化学生物学研究2019

    • Author(s)
      北将樹
    • Organizer
      第42回日本分子生物学会年会・シンポジウム『トキシン』の織りなす多元的世界
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Stylissatin Aの抗炎症及び抗肥満活性に関する研究2019

    • Author(s)
      張夢華, 砂場大輝, Yiting Sun, 柴田貴広, 佐々木一憲, 礒田博子, 木越英夫,北将樹
    • Organizer
      第61回天然有機化合物討論会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 切れ味の良い分子を自然界にもとめて2019

    • Author(s)
      北将樹
    • Organizer
      第1回名大・岐阜大農学シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Book] Discovery and use of natural products and derivatives as chemical probes. in The Discovery and Utility of Chemical Probes in Target Discovery, Eds. P. Brennan & S. V. Rodriguez2020

    • Author(s)
      Masaki Kita and Hideo Kigoshi
    • Total Pages
      26
    • Publisher
      The Royal Society of Chemistry
    • ISBN
      9781788015899
    • Related Report
      2020 Annual Research Report
  • [Remarks] 名古屋大学 生命農学研究科 天然物ケミカルバイオロジー研究室

    • URL

      https://mkita64.wixsite.com/mysite

    • Related Report
      2021 Annual Research Report
  • [Remarks] 名古屋大学 大学院生命農学研究科 天然物ケミカルバイオロジー研究室

    • URL

      https://mkita64.wixsite.com/mysite

    • Related Report
      2020 Annual Research Report
  • [Remarks] 名古屋大学 大学院生命農学研究科 天然物ケミカルバイオロジー研究室

    • URL

      http://www.agr.nagoya-u.ac.jp/~chembio/index.html

    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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