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Development of novel middle-molecule proteasome inhibitors and their drug delivery methods

Research Project

Project/Area Number 19K05739
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37030:Chemical biology-related
Research InstitutionNagahama Institute of Bio-Science and Technology

Principal Investigator

Hasegawa Makoto  長浜バイオ大学, バイオサイエンス学部, 教授 (10367899)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords進化分子工学 / プロテアソーム阻害剤 / 中分子医薬 / 分子進化工学
Outline of Research at the Start

創薬リードとしてペプチドなど中程度の分子量の化合物が再評価されている。細胞選択性・膜透過性・特異性・親和性などの機能を付与できるためであるが、その開発の方法論は発展途上である。本研究では、がん特異性、作用点への集積、酵素活性部位への移行を制御といった機能を持つペプチドを利用した低分子量の医薬候補の活性増強とドラッグデリバリーの手法を確立し、新しい中分子医薬の設計法を提案する。

Outline of Final Research Achievements

The purpose of this study is to develop a peptide-conjugated inhibitor that can act easily on the 26S proteasome. This peptide region is permeable to cell membranes and enhances its effect on drug-resistant cells. First, we searched for novel sequence peptides that bind to membrane proteins prominently expressed in colorectal cancer by cDNA display method. Next, peptides that accumulate on proteasomes were linked to proteasome inhibitor compounds with a molecular weight of about 500, and compounds were synthesized that internalize cell-specifically by receptor endocytosis and accumulate on their targets. The drug efficacy was further demonstrated by using colon cancer-derived cell lines as a model system to verify intracellular proteasome activity and other properties.

Academic Significance and Societal Importance of the Research Achievements

本研究では、プロテアソームの新しい制御機構を明らかにするために、ランダムペプチドライブラリーから20S PSに直接的な親和性を有するアミノ酸配列の探索を行った。得られたペプチドは、20S PSに対し非拮抗的に阻害作用を示した。その作用には疎水性アミノ酸を含む7残基の配列が重要であることを構造活性相関の検証により明らかにした。従来のプロテアソーム阻害剤が基質認識部位に直接作用するのに対し、これらのペプチドは全く異なるメカニズムで活性制御することから、新しいタイプのプロテアソーム阻害剤開発の手がかりになることが期待される。

Report

(3 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (6 results)

All 2022 2021

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (1 results) Book (1 results)

  • [Journal Article] Structure and Function of Potential Glycosylation Sites of Dynactin-Associated Protein dynAP2022

    • Author(s)
      Yin Xiaobo、Konishi Takayuki、Horikawa Kazuo、Tanaka Ryota、Togo Yuki、Noda Takanori、Hosoi Miho、Tsuchida Mie、Kunoh Tatsuki、Wada Shuichi、Nakamura Toshinobu、Tsuda Eisuke、Sasaki Ryuzo、Mizukami Tamio、Hasegawa Makoto
    • Journal Title

      Molecular Biotechnology

      Volume: 64 Issue: 6 Pages: 611-620

    • DOI

      10.1007/s12033-021-00435-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enrichment of Uncommon Bacteria in Soil by Fractionation Using a Metal Mesh Device2021

    • Author(s)
      KAMBA Seiji、OGURA Atsushi、MIURA Yoshiko、HASEGAWA Makoto
    • Journal Title

      Analytical Sciences

      Volume: 37 Issue: 9 Pages: 1295-1300

    • DOI

      10.2116/analsci.21P042

    • NAID

      130008087322

    • ISSN
      0910-6340, 1348-2246
    • Year and Date
      2021-09-10
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression and cell transformation activity of dynactin‐associated protein isoforms2021

    • Author(s)
      Yin Xiaobo、Yamada Shota、Kobayashi Hiroaki、Tanaka Ryota、Togo Yuki、Hosoi Miho、Tsuchida Mie、Kunoh Tatsuki、Wada Shuichi、Nakamura Toshinobu、Sasaki Ryuzo、Mizukami Tamio、Hasegawa Makoto
    • Journal Title

      FEBS Open Bio

      Volume: 11 Issue: 8 Pages: 2110-2117

    • DOI

      10.1002/2211-5463.13202

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of microparticle counting sensor based on structural and spectroscopic properties of metal mesh device.2021

    • Author(s)
      Hirokazu Seto, Atsushi Saiki, Ryosuke Matsushita, Wataru Mitsukami, Seiji Kamba, Makoto Hasegawa, Yoshiko Miura, Yumiko Hirohashi, Hiroyuki Shinto
    • Journal Title

      Advanced Powder Technology

      Volume: - Issue: 6 Pages: 1920-1926

    • DOI

      10.1016/j.apt.2021.04.002

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 膜結合型グアニル酸シクラーゼCに対する人工リガンドペプチドの探索2021

    • Author(s)
      髙橋由貴、落合慧璃、長谷川慎
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Book] 中分子創薬に向けたDDS開発の新展開2022

    • Author(s)
      杉林堅次
    • Total Pages
      239
    • Publisher
      シーエムシー出版
    • ISBN
      9784781316598
    • Related Report
      2021 Annual Research Report

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

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