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A novel mode of enzyme inhibition by molecular aggregation of low molecular weight compounds

Research Project

Project/Area Number 21K18850
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 27:Chemical engineering and related fields
Research InstitutionKobe University

Principal Investigator

MARUYAMA TATSUO  神戸大学, 工学研究科, 教授 (30346811)

Co-Investigator(Kenkyū-buntansha) 青井 貴之  神戸大学, 科学技術イノベーション研究科, 教授 (00546997)
Project Period (FY) 2021-07-09 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords低分子 / 凝集 / 酵素阻害 / DNA分解酵素 / 溶解度 / 分子凝集 / 酵素 / 阻害 / 分子集合化 / 選択性
Outline of Research at the Start

本研究では、化合物分子の凝集が引き起こす全く新しい酵素阻害機構の解明に挑戦する。申請者らは、ある多環式低分子化合物(化合物1)がその溶解度を超えて不溶になり始めると、DNA分解酵素に対する阻害活性が現れることを発見した。本研究で明らかにする酵素阻害機構は、1分子では特段の機能を持たない低分子化合物が分子レベルで凝集し、この凝集体が核酸分解酵素(DNase)に対して阻害活性を示すという全く新しいものである。申請者らは本研究を通して、1分子では特段の機能を持たない低分子化合物が凝集することで酵素阻害機能を発揮することを明らかにし、この新しい酵素阻害機構が新しい創薬戦略となりうることを実証する。

Outline of Final Research Achievements

The mechanism of enzyme inhibition by an inhibitor is commonly recognized as a one-on-one reaction. However, we discovered a small molecule that inhibits an enzyme in a many-on-one manner. Mn007 is a small molecule compound reported in 2015 as a candidate for muscular dystrophy therapeutics. We found that when Mn007 exceeded its water solubility and became insoluble, it exhibited the inhibitory activity against DNase I. When cyclodextrin was used to solubilize Mn007 aggregates in water, the inhibitory effect disappeared. Microscopic observation also confirmed the interaction of Mn007 aggregates with DNase I. The various investigations revealed that the aggregation of Mn007 molecules was important for the inhibition of DNase I. Our finding would open up a new field in drug discovery.

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまで想定されていなかった阻害剤分子多数対酵素一分子という阻害様式を発見した。このことは生化学分野における酵素阻害の認識を大きく広げるものである。酵素阻害は創薬と深く関連するからである。またこれまで難しかったDNA分解酵素の阻害を実証できたことは大きい。これを元により実用的なDNA分解酵素阻害剤の開発につながる可能性がある。特に、DNA分解酵素は溶連菌感染症と深く関わっているため、実用的なDNA分解酵素阻害剤の開発はこれまで有効な手立てがなかった劇症型溶血性連鎖球菌の薬になる可能性を秘めている。

Report

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

    (11 results)

All 2023 2022 2021

All Journal Article (5 results) (of which Peer Reviewed: 5 results) Presentation (6 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Journal Article] Thermally irreversible supramolecular hydrogels record thermal history2023

    • Author(s)
      Tominaga Yudai、Kanemitsu Sayuki、Yamamoto Shota、Kimura Toshihisa、Nishida Yuki、Morita Kenta、Maruyama Tatsuo
    • Journal Title

      Colloids and Surfaces A: Physicochemical and Engineering Aspects

      Volume: 656 Pages: 130416-130416

    • DOI

      10.1016/j.colsurfa.2022.130416

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Micelle-like Nanoassemblies of Short Peptides Create Antimicrobial Selectivity in a Conventional Antifungal Drug2022

    • Author(s)
      Morita Kenta、Nishimura Yuya、Ishii Jun、Maruyama Tatsuo
    • Journal Title

      ACS Applied Nano Materials

      Volume: 6 Issue: 2 Pages: 1432-1440

    • DOI

      10.1021/acsanm.2c05183

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of Melittin Activity Using a Small Molecule with an Indole Ring2022

    • Author(s)
      S. Kanemitsu, K. Morita, Y. Tominaga, K. Nishimura, T. Yashiro, H. Sakurai, Y. Yamamoto, I. Kurisaki, S. Tanaka, M. Matsui, T. Ooya, A. Tamura, and T. Maruyama
    • Journal Title

      J. Phys. Chem. B

      Volume: 126 Issue: 31 Pages: 5793-5802

    • DOI

      10.1021/acs.jpcb.2c03595

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In Situ Synthesis of an Anticancer Peptide Amphiphile Using Tyrosine Kinase Overexpressed in Cancer Cells2022

    • Author(s)
      Morita Kenta、Nishimura Kanon、Yamamoto Shota、Shimizu Natsumi、Yashiro Tomoko、Kawabata Ryoko、Aoi Takashi、Tamura Atsuo、Maruyama Tatsuo
    • Journal Title

      JACS Au

      Volume: 2 Issue: 9 Pages: 2023-2028

    • DOI

      10.1021/jacsau.2c00301

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rewritable Surface on a Plastic Substrate Using Fluorous Affinity2021

    • Author(s)
      Tsuchii Takane、Kaneko Kazuki、Morita Kenta、Nishino Takashi、Maruyama Tatsuo
    • Journal Title

      ACS Applied Materials & Interfaces

      Volume: 14 Issue: 2 Pages: 3255-3263

    • DOI

      10.1021/acsami.1c18633

    • NAID

      120007188911

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] がん細胞内過剰発現キナーゼによる抗がんペプチド脂質の合成とがん細胞の殺傷2023

    • Author(s)
      丸山達生, 西村香音, 森田健太, 山本翔太, 清水なつみ, 青井貴之, 田村厚夫
    • Organizer
      化学工学会第88年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 酵素を阻害する凝集性低分子2023

    • Author(s)
      森田 健太, 青井 貴之, 池田 真理子, 丸山 達生
    • Organizer
      化学工学会第88年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Intracellular Synthesis of a Self-Assembling Peptide Amphiphile to Selectively Kill Cancer Cells Overexpressing Tyrosine Kinase2022

    • Author(s)
      Kanon Nishimura, Kenta Morita, Shota Yamamoto, Natsumi Shimizu, Takashi Aoi, and Tatsuo Maruyama
    • Organizer
      The Pacific Polymer Conference 17
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hydrolysis of amide bonds of foreign molecules using self-assembly of peptide lipids2022

    • Author(s)
      Toshihisa Kimura, Natsumi Shimizu, Kenta Morita and Tatsuo Maruyama
    • Organizer
      The Pacific Polymer Conference 17
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Induction of cancer cell apoptosis using an overexpressed kinase and a peptide lipid2022

    • Author(s)
      Natsumi Shimizu, Sayuki Kanemitsu, Tomoko Yashiro, Kenta Morita, Takashi Aoi, Tatsuo Maruyama
    • Organizer
      The 14th Japan-Korea Symposium on Materials and Interfaces
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Selective death of cancer cells using the overexpressed kinase and a peptide lipid2022

    • Author(s)
      Natsumi Shimizu, Sayuki Kanemitsu, Tomoko Yashiro, Kenta Morita, Takashi Aoi, Tatsuo Maruyama
    • Organizer
      The Pacific Polymer Conference 17
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research

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Published: 2021-07-13   Modified: 2025-03-27  

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