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Development of novel middle molecular weight anticancer agents based on proteasome inhibition

Research Project

Project/Area Number 16K08329
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Drug development chemistry
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) 2016-10-21 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsプロテアソーム阻害剤 / 膜透過ペプチド / 薬剤耐性骨髄腫 / 膜透過性ペプチド / 分子進化工学 / 中分子医薬 / ケミカルバイオロジー
Outline of Final Research Achievements

Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. We prepared several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. We infer that the R8 peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. Thus, conjugation of nonpeptidic proteasome inhibitors with a cell-penetrating peptide a viable strategy to overcome drug-resistance of tumor cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、新規化合物リダイフェン-F (RID-F)の構造活性相関を検討した結果、阻害活性の最小構造を見出した。RID-Fは、ヒト培養細胞に対してユビキチン修飾タンパク質の蓄積とアポトーシス誘導を引き起こした。しかし、その効果は比較的高容量を必要とした。そこで、RID-Fに細胞膜透過ペプチドの付加を検討した。これは細胞膜透過のみならず26Sプロテアソームに対する阻害活性を増強し、多剤耐性を示す骨髄腫細胞株に対して細胞死を誘導した。以上の結果から、薬効改善のための合理的な構造デザイン法を提示し、中程度の分子量を持つ化合物による新しい創薬の戦略を提示した。

Report

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

    (6 results)

All 2019 2018 2017

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (3 results)

  • [Journal Article] Amplification of Sensor Signals from Metal Mesh Device with Fine Periodic Structure2019

    • Author(s)
      Seto, H., Saiki, A., Kamba, S., Kondo, T., Hasegawa, M., Miura, Y., Hirohashi, Y. and Shinto, H.
    • Journal Title

      Analytical Sciences

      Volume: 35 Issue: 6 Pages: 619-623

    • DOI

      10.2116/analsci.18P498

    • NAID

      130007661685

    • ISSN
      0910-6340, 1348-2246
    • Year and Date
      2019-06-10
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human alcohol dehydrogenase 1 is an acceptor protein for polyADP-ribosylation.2019

    • Author(s)
      Yamashita, S., Tanaka, M., Nodono, H., Hamada, A., Hamada, T., Hasegawa, M., Nishi, Y., Moss, J., Miwa, M.
    • Journal Title

      Biochemical Pharmacology

      Volume: 印刷中 Pages: 27-32

    • DOI

      10.1016/j.bcp.2019.03.037

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death.2018

    • Author(s)
      Tanaka, M., Zhu, Y., Shionyu, M., Ota, N., Shibata, N., Watanabe, C., Mizusawa, A., Sasaki, R., Mizukami, T., Shiina, I., Hasegawa, M.
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 146 Pages: 636-650

    • DOI

      10.1016/j.ejmech.2018.01.045

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] プロテアソーム阻害剤リダイフェン-Fへの膜透過性ペプチド付加による多剤耐性型骨髄腫細胞株への作用増強2018

    • Author(s)
      田中誠、朱耘浩、塩生真史、太田のぞみ、芝田夏実、渡邊千尋、水澤彰人、佐々木隆造、水上民夫、椎名勇、長谷川慎
    • Organizer
      日本ケミカルバイオロジー学会第13回年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 細胞膜透過ペプチドコンジュゲートによるタモキシフェン誘導体RID-Fの26Sプロテアソーム阻害効果の向上2017

    • Author(s)
      田中誠、朱耘浩、太田のぞみ、芝田夏実、椎名勇、佐々木隆造、 水上民夫、長谷川慎
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] 進化分子工学的手法によるプロテアソーム阻害ペプチドの探索と構造活性相関研究2017

    • Author(s)
      朱耘浩,田中誠,早川結実子,小牧明日美,北村幸一郎,水上民夫,長谷川慎
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report

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Published: 2016-10-24   Modified: 2020-03-30  

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