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Structural Control and Generation of New Functional Molecules Using a Solid-Phase Library Strategy for Peptidic Natural Products

Research Project

Project/Area Number 21K05286
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
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), 准教授 (20758205)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords天然物有機化学 / 化合物ライブラリー / 固相合成 / 構造活性相関 / 全合成
Outline of Research at the Start

本研究は、FoF1-ATP合成酵素を標的とする天然物の精密な構造制御とこれに基づく新機能創製を目的とする。固相合成法を応用した天然物類縁体ライブラリーの構築と、生物機能評価ならびに構造決定により、構造活性相関情報の取得と新規機能制御分子の創出を目指す。

Outline of Final Research Achievements

The aim of this study is the generation of new functional molecules through the structural modification of natural products targeting FoF1-ATP synthase. A complex peptidic natural product efrapeptin C was adopted as the structural basis, and the introduction of a methyl group, the smallest aliphatic substituent, was conducted to enhance the biological activity by controlling its three-dimensional structure.
First, an efficient strategy for the solid-phase total synthesis of efrapeptin C was established. Using this synthetic strategy, six methylated analogues were constructed, and their biological activities and molecular functions were evaluated. As a result, a promising new analogue was discovered. This new analogue exhibited more potent growth inhibitory activity against cancer cells and higher proteolytic stability compared to the parent efrapeptin C.

Academic Significance and Societal Importance of the Research Achievements

メチル基導入は、医薬品候補化合物の特性を最適化するために広く用いられているが、柔軟かつ分子量の大きい鎖状分子においては、導入する位置や立体化学の生物活性に与える総合的影響を正確に予測することは困難であり、応用例が限られてきた。また、一般的に自然選択を経た生物活性天然物よりも優れた性質を示す類縁体を得ることは容易ではない。強力な活性と高い安定性を持つ新規エフラペプチンC類縁体の創出に成功した本成果は、鎖状分子を対象とした機能向上の方法論として、メチル基導入による構造制御が有効であることを実証する重要なものである。また、得られた類縁体は、新規抗がん活性分子創出のために有用な構造基盤である。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (48 results)

All 2024 2023 2022 2021 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: 7 results) Presentation (27 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results) Book (1 results) Remarks (5 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] IST Austria(オーストリア)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Massachusetts Institute of Technology(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Technion(イスラエル)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Construction of Five Tryptophan Isomers and Application of the Isomers to Solid-Phase Total Syntheses of Lysocin E Derivatives2023

    • Author(s)
      Yosuke Nakata, Junhao Fu, Hiroaki Itoh, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue
    • Journal Title

      Chemistry - A European Journal

      Volume: 29 Issue: 43

    • DOI

      10.1002/chem.202301225

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular Editing Enhances Oxidation Resistance of Menaquinone-Targeting Antibiotics Lysocin E and WAP-8294A22023

    • Author(s)
      Junhao Fu, Yosuke Nakata, Hiroaki Itoh, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue
    • Journal Title

      Chemistry - A European Journal

      Volume: 29 Issue: 47

    • DOI

      10.1002/chem.202301224

    • URL

      https://pure.teikyo.jp/en/publications/6656318f-50f3-4f57-8f42-174626fa1921

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] C-Terminal modification of polytheonamide B uncouples its dual functions in MCF-7 cancer cells2023

    • Author(s)
      Yun-Wei Xue, Kensuke Miura, Hiroaki Itoh, Masayuki Inoue
    • Journal Title

      Chemical Communications

      Volume: 59 Issue: 26 Pages: 3914-3917

    • DOI

      10.1039/d2cc05915k

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Total Synthesis and Functional Analysis of Complex Peptidic Natural Products and Their Artificial Analogues2022

    • Author(s)
      Hiroaki Itoh
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 142 Issue: 6 Pages: 561-571

    • DOI

      10.1248/yakushi.22-00042

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2022-06-01
    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gramicidin A accumulates in mitochondria, reduces ATP levels, induces mitophagy, and inhibits cancer cell growth2022

    • Author(s)
      Yun-Wei Xue, Hiroaki Itoh, Shingo Dan, Masayuki Inoue
    • Journal Title

      Chemical Science

      Volume: 13 Issue: 25 Pages: 7482-7491

    • DOI

      10.1039/d2sc02024f

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a High-Throughput Strategy for Functional Enhancement and Alteration of Antibacterial Natural Products2021

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

      Journal of Synthetic Organic Chemistry, Japan

      Volume: 79 Issue: 11 Pages: 996-1004

    • DOI

      10.5059/yukigoseikyokaishi.79.996

    • NAID

      130008114788

    • ISSN
      0037-9980, 1883-6526
    • Year and Date
      2021-11-01
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum apolipoprotein A-I potentiates the therapeutic efficacy of lysocin E against Staphylococcus aureus2021

    • Author(s)
      Hiroshi Hamamoto*, Suresh Panthee*, Atmika Paudel, Kenichi Ishii, Jyunichiro Yasukawa, Su Jie, Atsushi Miyashita, Hiroaki Itoh, Kotaro Tokumoto, Masayuki Inoue, Kazuhisa Sekimizu
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6364-6364

    • DOI

      10.1038/s41467-021-26702-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 18O/16O‐Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products2021

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

      Chemistry - An Asian Journal

      Volume: 16 Issue: 17 Pages: 2447-2452

    • DOI

      10.1002/asia.202100674

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Generation and Biological Evaluation of Degraded Derivatives of the Three E/Z-Isomers of Yaku’amide B2021

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

      Journal of Natural Products

      Volume: 84 Issue: 6 Pages: 1854-1859

    • DOI

      10.1021/acs.jnatprod.1c00339

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Preparation of Hindered Aniline CyanH and Application in the Allyl-Ni-Catalyzed α,β-Dehydrogenation of Carbonyls2021

    • Author(s)
      Submitted by Alexandra K. Bodnar, Aneta Turlik, David Huang, Will Butcher, Joanna K. Lew, and Timothy R. Newhouse, Checked by Aoi Takeuchi, Hiroaki Itoh, Masayuki Inoue
    • Journal Title

      Organic Syntheses

      Volume: 98 Pages: 263-288

    • DOI

      10.15227/orgsyn.098.0263

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] 固相全合成を基盤としたペプチド系複雑天然物の構造多様化と機能向上2024

    • Author(s)
      伊藤 寛晃
    • Organizer
      日本薬学会 第144年会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 海洋産シデロフォア ロイヒケリンCおよび人工類縁体の固相全合成と機能解析2024

    • Author(s)
      澤田 瑞希、柿澤 大夢、竹内 碧、伊藤 寛晃、井上 将行
    • Organizer
      日本薬学会 第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] グラミシジンAトリプトファン残基の位置異性体への置換による機能改変2024

    • Author(s)
      右田貴大、伊藤寛晃、井上将行
    • Organizer
      日本薬学会 第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 複雑ペプチド系天然物を基盤とした新規生物活性分子の創出戦略2023

    • Author(s)
      伊藤 寛晃
    • Organizer
      第10回慶應有機化学若手シンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Bioactivity Enhancement by Structural Modification of an Anticancer Natural Product Efrapeptin C2023

    • Author(s)
      林 元棋、伊藤 寛晃、井上 将行
    • Organizer
      第21回次世代を担う有機化学シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] 複雑ペプチド系天然物ヤクアミドBのOne-Bead-One-Compound戦略による構造単純化2023

    • Author(s)
      伊藤 寛晃、三浦 健介、井上 将行
    • Organizer
      日本ケミカルバイオロジー学会 第17回年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 天然物の構造多様化を基盤とした新規生物活性分子の創出戦略2023

    • Author(s)
      伊藤 寛晃
    • Organizer
      第56回天然物化学談話会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] グラミシジンAトリプトファン改変体の合成と機能向上2023

    • Author(s)
      右田貴大、薛贇唯、伊藤寛晃、井上将行
    • Organizer
      第56回天然物化学談話会
    • Related Report
      2023 Annual Research Report
  • [Presentation] グラミシジンAトリプトファン改変体の合成と機能向上2023

    • Author(s)
      右田貴大、薛贇唯、伊藤寛晃、井上将行
    • Organizer
      第67回日本薬学会関東支部大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 天然物の構造多様化を基盤とした新規生物活性分子の創出戦略2023

    • Author(s)
      伊藤 寛晃
    • Organizer
      化生談話会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] ロイヒケリンCの固相全合成2023

    • Author(s)
      柿澤 大夢、澤田 瑞希、竹内 碧、伊藤 寛晃、井上 将行
    • Organizer
      日本薬学会 第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] エフラペプチンCおよび類縁体の固相全合成と機能解析2023

    • Author(s)
      林 元棋、伊藤 寛晃、井上 将行
    • Organizer
      日本薬学会 第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] One-bead-one-compound戦略によるヤクアミドBの構造単純化2023

    • Author(s)
      三浦 健介、伊藤 寛晃、井上 将行
    • Organizer
      日本薬学会 第143年会
    • Related Report
      2022 Research-status Report
  • [Presentation] ロイヒケリンCの固相全合成研究2022

    • Author(s)
      柿澤大夢、竹内碧、伊藤寛亮、井上将行
    • Organizer
      第82回有機合成化学協会関東支部シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] ヤクアミドB類縁体OBOCライブラリーの構築・評価法の開発2022

    • Author(s)
      三浦健介、伊藤寛晃、井上将行
    • Organizer
      第21回東京大学生命科学シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] Solid-Phase Total Synthesis and Functional Analysis of Yaku'amide B and Its Analogues2022

    • Author(s)
      Hiroaki Itoh, Masayuki Inoue
    • Organizer
      ICCEOCA-15
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] エフラペプチンCおよび類縁体の固相全合成と機能解析2022

    • Author(s)
      林 元棋、伊藤 寛晃、井上 将行
    • Organizer
      第66回薬学会関東支部大会
    • Related Report
      2022 Research-status Report
  • [Presentation] Synthetic Study of Delftibactin A2022

    • Author(s)
      Aoi Takeuchi, Hiromu Kakizawa, Hiroaki Itoh, Masayuki Inoue
    • Organizer
      第13回大津会議
    • Related Report
      2022 Research-status Report
  • [Presentation] Functional Analysis of an Ion-Channel-Forming Peptidic Natural Product Gramicidin A2022

    • Author(s)
      Hiroaki Itoh, Yun-Wei Xue, Masayuki Inoue
    • Organizer
      第59回ペプチド討論会
    • Related Report
      2022 Research-status Report
  • [Presentation] キノン認識ペプチド系天然物のトリプトファン残基改変体の全合成と機能解析2022

    • Author(s)
      中田遥友、付俊豪、伊藤寛晃、井上将行
    • Organizer
      第48回反応と合成の進歩シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] イオンチャネル形成天然物グラミシジンAの機能解析2022

    • Author(s)
      薛贇唯,伊藤寛晃,井上将行
    • Organizer
      日本薬学会 第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 合成プローブを利用したヤクアミドBの生物活性発現機構解析2022

    • Author(s)
      神谷光一,喜多村佳委,伊藤寛晃,櫻井香里,井上将行
    • Organizer
      日本薬学会 第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] WAP-8294A2トリプトファン類縁体の合成と機能解析2022

    • Author(s)
      中田遥友,伊藤寛晃,井上将行
    • Organizer
      日本薬学会 第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] OBOCライブラリー戦略に基づくペプチド系天然物の機能制御2021

    • Author(s)
      伊藤寛晃,井上将行
    • Organizer
      第65回日本薬学会関東支部大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] ライソシンEトリプトファン残基改変体の設計,合成および機能解析2021

    • Author(s)
      付 俊豪,中田 遥友,伊藤 寛晃,井上 将行
    • Organizer
      第63回天然有機化合物討論会
    • Related Report
      2021 Research-status Report
  • [Presentation] 18O/16O-encoding strategy for microscale stereochemical determination of peptidic natural products2021

    • Author(s)
      竹内碧,伊藤寛晃,井上将行
    • Organizer
      AIMECS2021
    • Related Report
      2021 Research-status Report
  • [Presentation] Solid-Phase Total Synthesis and Target Identification of Yaku'amide B2021

    • Author(s)
      Hiroaki Itoh, Masayuki Inoue
    • Organizer
      Pacifichem2021
    • Related Report
      2021 Research-status Report
  • [Book] Discovery of Natural Product Analogues with Altered Activities by a High-Throughput Strategy, In New Tide of Natural Product Chemistry (H. Ishikawa and H. Takayama, eds.)2023

    • Author(s)
      Hiroaki Itoh
    • Total Pages
      22
    • Publisher
      Springer, Singapore
    • ISBN
      9789819917136
    • Related Report
      2023 Annual Research 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

      https://inoue.f.u-tokyo.ac.jp/index.html

    • Related Report
      2023 Annual Research Report 2021 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

      https://inoue.f.u-tokyo.ac.jp/

    • Related Report
      2022 Research-status Report
  • [Remarks] 薬学部トピックス(2022/6/6)

    • URL

      https://www.f.u-tokyo.ac.jp/topics.html?page=1&key=1654503399

    • Related Report
      2022 Research-status Report
  • [Remarks] 薬学部トピックス(2021/11/8)

    • URL

      https://www.f.u-tokyo.ac.jp/topics.html?page=1&key=1636371110

    • Related Report
      2021 Research-status Report
  • [Remarks] 薬学部トピックス(2021/7/29)

    • URL

      https://www.f.u-tokyo.ac.jp/topics.html?page=2&key=1627555517

    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] ペプチド系抗がん活性化合物2023

    • 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
    • Filing Date
      2023
    • Related Report
      2023 Annual Research Report
  • [Patent(Industrial Property Rights)] Anticancer compound2022

    • Inventor(s)
      Masayuki Inoue, Hiroaki Itoh
    • Industrial Property Rights Holder
      The University of Tokyo
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2022 Research-status Report
    • Overseas

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Published: 2021-04-28   Modified: 2025-01-30  

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