• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Comprehensive structure-activity relationship study of large and complex peptidic natural products

Research Project

Project/Area Number 17K15421
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Chemical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

Itoh Hiroaki  東京大学, 大学院薬学系研究科(薬学部), 助教 (20758205)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords有機化学 / 構造活性相関 / 固相合成 / ペプチド / ケミカルバイオロジー / 生物機能分子 / 天然物 / 全合成 / コンビナトリアル化学 / ライブラリー / スクリーニング / 合成化学 / コンビナトリアルケミストリー
Outline of Final Research Achievements

In this study, solid-phase total synthesis of a peptide antibiotic WAP-8294A2 was achieved. Further functional evaluation revealed the antimicrobial activity of WAP-8294A2 is due to their membrane-disrupting effects depend on the presence of menaquinone. We also achieved solid-phase total synthesis of a channel-forming peptide polytheonamide B, which enabled the investigation of the mechanism of action. The addition of polytheonamide B to MCF-7 cells rapidly diminished a potential across the plasma membrane. Furthermore, polytheonamide B was found to be internalized into the cells, accumulating in lysosomes and neutralizing the lysosomal pH gradient. In addition, the cellular target of yaku’amide B was elucidated. Pull-down assays with biotinylated probes revealed FoF1-ATP synthase as the major target protein of yaku’amide B.

Academic Significance and Societal Importance of the Research Achievements

本研究では、顕著な抗菌活性、抗がん活性などの極めて重要な生物活性を示す中・大型複雑構造ペプチド天然物に該当する複数の化合物および類縁体の合成的供給法を確立した。ここで見出された方法論は、他の中・大型複雑構造ペプチドの合成にも直接的に応用可能であり、これら化合物群の持つ機能解析ならびに類縁体合成へ資することが期待される。また、これら化合物の持つ分子機能ならびに特異な作用機構を明らかにしたことで、中・大型複雑構造ペプチドの構成する化学空間の潜在的有用性を示した。以上より、本成果は将来的に有用な新規医薬品シーズの発見へも寄与しうる、薬学、有機化学を含む広範な領域に対して意義を有するものである。

Report

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

    (29 results)

All 2019 2018 2017 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (21 results) (of which Int'l Joint Research: 8 results,  Invited: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Comprehensive Structure-Activity Relationship Studies of Macrocyclic Natural Products Enabled by Their Total Syntheses2019

    • Author(s)
      Itoh Hiroaki、Inoue Masayuki
    • Journal Title

      Chemical Reviews

      Volume: 印刷中 Issue: 17 Pages: 10002-10031

    • DOI

      10.1021/acs.chemrev.9b00063

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Solid-Phase Total Synthesis and Dual Mechanism of Action of the Channel-Forming 48-mer Peptide Polytheonamide B2018

    • Author(s)
      Hayata Atsushi、Itoh Hiroaki、Inoue Masayuki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 140 Issue: 33 Pages: 10602-10611

    • DOI

      10.1021/jacs.8b06755

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Target Identification of Yaku’amide B and Its Two Distinct Activities against Mitochondrial FoF1-ATP Synthase2018

    • Author(s)
      Kitamura Kai、Itoh Hiroaki、Sakurai Kaori、Dan Shingo、Inoue Masayuki
    • Journal Title

      Journal of the American Chemical Society

      Volume: 140 Issue: 38 Pages: 12189-12199

    • DOI

      10.1021/jacs.8b07339

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Total Synthesis and Biological Evaluation of 19-Hydroxysarmentogenin-3-O-α-l-rhamnoside, Trewianin, and Their Aglycons2018

    • Author(s)
      Urabe Daisuke、Nakagawa Yuki、Mukai Ken、Fukushima Kei-ichiro、Aoki Naoto、Itoh Hiroaki、Nagatomo Masanori、Inoue Masayuki
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 83 Issue: 22 Pages: 13888-13910

    • DOI

      10.1021/acs.joc.8b02219

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deuteration and Selective Labeling of Alanine Methyl Groups of β 2-Adrenergic Receptor Expressed in a Baculovirus-Insect Cell Expression System2018

    • Author(s)
      Yutaka Kofuku, Tomoki Yokomizo, Shunsuke Imai, Yutaro Shiraishi, Mei Natsume, Hiroaki Itoh, Masayuki Inoue, Kunio Nakata, Shunsuke Igarashi, Hideyuki Yamaguchi, Toshimi Mizukoshi, Ei-Ichiro Suzuki, Takumi Ueda, Ichio Shimada
    • Journal Title

      Journal of Biomolecular NMR

      Volume: 印刷中 Issue: 3 Pages: 185-192

    • DOI

      10.1007/s10858-018-0174-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone-Targeting Antibiotic2017

    • Author(s)
      Hiroaki Itoh, Kotaro Tokumoto, Takuya Kaji, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 83 Issue: 13 Pages: 6924

    • DOI

      10.1021/acs.joc.7b02318

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ヤクアミドBの標的タンパク質同定2019

    • Author(s)
      伊藤寛晃
    • Organizer
      LiHub創薬技術革新グループ ワークショップ 創薬関連研究の最先端
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Target Identification of Anticancer Natural Product Yaku'amide B2019

    • Author(s)
      Hiroaki Itoh
    • Organizer
      The Third A3 Young Scientist Meeting
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ライソシンEを基盤としたOBOCライブラリーの構築とスクリーニング2019

    • Author(s)
      徳本皓太郎、加治拓哉、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ポリセオナミド模倣ペプチドの作用解析2019

    • Author(s)
      薛贇唯、早田敦、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヤクアミドB類縁体の生物活性2019

    • Author(s)
      神谷光一、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] フラグメント連結によるヤクアミドBの固相全合成2019

    • Author(s)
      三浦健介、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヤクアミドBの固相全合成研究2018

    • Author(s)
      三浦健介、伊藤寛晃、井上将行
    • Organizer
      第53回天然物化学談話会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 抗がん活性天然物ヤクアミドBの標的タンパク質同定2018

    • Author(s)
      伊藤寛晃、喜多村佳委、櫻井香里、井上将行
    • Organizer
      第60回天然有機化合物討論会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Solid-Phase Total Synthesis and Biological Action of Polytheonamide B2018

    • Author(s)
      Hiroaki Itoh, Atsushi Hayata, Masayuki Inoue
    • Organizer
      The 13th International Conference on Cutting-Edge Organic Chemistry in Asia (ICCEOCA-13)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ポリセオナミド模倣ペプチドの作用解析2018

    • Author(s)
      薛贇唯,早田敦,伊藤寛晃,井上将行
    • Organizer
      第44回反応と合成の進歩シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Generation and Screening of Gramicidin A-Based Library2018

    • Author(s)
      Yuri Takada, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      10th International Peptide Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Unified Total Synthesis of Yaku'amide B and Its Analogues2018

    • Author(s)
      Koichi Kamiya, Tomoya Yamashita, Kensuke Miura, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      10th International Peptide Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ポリセオナミドBの細胞内動的挙動および作用解析2018

    • Author(s)
      早田敦、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヤクアミドBとその類縁体の統一的固相全合成2018

    • Author(s)
      神谷光一、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Total Synthesis and Biological Mode of Action of WAP-8294A2: A Menaquinone Targeting Antibiotic2017

    • Author(s)
      Hiroaki Itoh, Kotaro Tokumoto, Takuya Kaji, Masayuki Inoue
    • Organizer
      Chirality 2017 ISCD-29
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive Structure-Activity Relationship Study of Gramicidin A2017

    • Author(s)
      Yuri Takada, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      CiMR-UTokyo Symposium 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive Structure-Activity Relationship Study of Gramicidin A2017

    • Author(s)
      Yuri Takada, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      Dundee-Tokyo Postgraduate Research Symposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive Structure-Activity Relationship Study of Gramicidin A2017

    • Author(s)
      Yuri Takada, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      University of Strathclyde - University of Tokyo, 2017 Student Symposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comprehensive Structure-Activity Relationship Study of Gramicidin A2017

    • Author(s)
      Yuri Takada, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      KCL-Institute of Psychiatry, Psychology & Neuroscience - UT-GPLLI Joint Symposium
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] グラミシジン A 類縁体のライブラリー構築とスクリーニング法開発2017

    • Author(s)
      高田悠里、伊藤寛晃、井上将行
    • Organizer
      第35回メディシナルケミストリーシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 抗がん活性天然物ヤクアミドBの作用機構解明2017

    • Author(s)
      喜多村佳委、伊藤寛晃、櫻井香里、井上将行
    • Organizer
      第43回反応と合成の進歩シンポジウム
    • Related Report
      2017 Research-status Report
  • [Remarks] 東京大学大学院薬学系研究科天然物合成化学教室ホームページ

    • URL

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

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 環状ペプチド系抗菌化合物2019

    • Inventor(s)
      井上将行、伊藤寛晃
    • Industrial Property Rights Holder
      井上将行、伊藤寛晃
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-033041
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi