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Studies on the active site-directed plasmin inhibitor: It may control plasmin having multifunctional properties

Research Project

Project/Area Number 25460164
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Drug development chemistry
Research InstitutionKobe Gakuin University

Principal Investigator

TSUDA YUKO  神戸学院大学, 薬学部, 教授 (10098478)

Co-Investigator(Kenkyū-buntansha) HIDAKA KOUSHI  神戸学院大学, 薬学部, 講師 (30445960)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2013: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywordsプラスミン / 阻害剤 / 活性部位指向型 / 炎症性疾患治療薬 / P1’ 残基 / P2残基 / 酵素選択性
Outline of Final Research Achievements

Plasmin (PL) plays a dominant role in the fibrinolysis pathway so that PL inhibitors have been used as a hemostatic agent. Additionally, PL is activated in specific regions of the extracellular milieu to digest many proteins on the localized cell surface resulting in inducing cell inversion and metastasis and alternating the expression of cytokines. In this work, we disclosed 1) PL inhibitor (YO-2) attenuated both aGVHD- and colitis-associated lethality in mice; 2) more potent and selective PL inhibitor was obtained.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (26 results)

All 2016 2015 2014 2013 Other

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Acknowledgement Compliant: 3 results,  Open Access: 2 results) Presentation (15 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Remarks (3 results)

  • [Journal Article] Active site-directed plasmin inhibitors: Extension on the P2 residue.2016

    • Author(s)
      K. Hidaka, K. Gohda, N. Teno, K. Wanaka, Y. Tsuda.
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 24 Pages: 545-553

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Design of plasmin inhibitors targeting the S1’subsite.2016

    • Author(s)
      M. Kusano, K. Hidaka, K. Gohda, N. Teno, K. Wanaka, Y. Tsuda
    • Journal Title

      Peptide Science 2015

      Volume: 2015 Pages: 143-144

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Novel type of plasmin inhibitors: Providing insight into P4 moiety and alternative scaffold to pyrrolopyrimidine.2015

    • Author(s)
      N. Teno, K, Gohda, K. Wanaka, Y. Tsuda, M. Akagawa, E. Akiduki, M. Araki, Masuda A. Masuda, T. Otsubo, Y. Yamashita.
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 23 Issue: 13 Pages: 3696-3704

    • DOI

      10.1016/j.bmc.2015.04.013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking.2015

    • Author(s)
      A Sato, C Nishida, K Sato-Kusubata, M Ishihara, Y Tashiro, I Gritli, H Shimazu, S Munakata, H Yagita, K Okumura, Y Tsuda, Y Okada, A Tojo, H Nakauchi, S Takahashi, B Heissig and K Hattori
    • Journal Title

      Leukemia

      Volume: 29 Issue: 1 Pages: 145-56

    • DOI

      10.1038/leu.2014.151

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9-Mediated Cytokine Release From Myeloid Cells.2015

    • Author(s)
      Munakata S, Tashiro Y, Nishida C, Sato A, Komiyama H, Shimazu H, Dhahri D, Salama Y, Eiamboonsert S, Takeda K, Yagita H, Tsuda Y, Okada Y, Nakauchi H, Sakamoto K, Heissig B, Hattori K.
    • Journal Title

      Gastroenterology

      Volume: 148 Issue: 3 Pages: 565-78

    • DOI

      10.1053/j.gastro.2014.12.001

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Study on the plasmin inhibitors: Replacement of the P2 and P1’ residues2015

    • Author(s)
      Suzuki A, Hidaka K, Gohda K, Teno N, Wanaka K, Tsuda Y.
    • Journal Title

      Peptide Science 2014

      Volume: 2015 Pages: 209-210

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Synthetic substrates specific to activated plasmin can monitor the enzymatic functional status in situ in breast cancer cells2014

    • Author(s)
      Gohda, K., Fujimori, K., Teno, N., Wanaka, K., and Tsuda, Y.
    • Journal Title

      Chem. Biol. Drug Des.

      Volume: 83 Issue: 1 Pages: 52-57

    • DOI

      10.1111/cbdd.12232

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pyrrolpyridine-inhibitors with hydantoin moiety as spacer can explore P4/S4 interaction on plasmin.2014

    • Author(s)
      Teno N, Gohda K, Wanaka K, Tsuda Y, Sueda T, Yamashita Y, Otsubo T.
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 22 Pages: 2339-2352

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] S1サブサイトを標的としたプラスミン阻害剤の探索2016

    • Author(s)
      村本凌太郎、日高興士、合田圭吾、手納直規、和中敬子、津田裕子
    • Organizer
      日本薬学会135年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] Active site directed plasmin inhibitors: modification on P1’ residue2015

    • Author(s)
      M. Kusano, A. Suzuki, K. Hidaka, K. Gohda, N. Teno, K. Wanaka, Y. Tsuda
    • Organizer
      7th International peptide symposium 2015
    • Place of Presentation
      Singapore
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規プラスミン阻害剤への展開:pyrrolopyrimidine scaffoldからbenzimidazole scaffoldへの変換2015

    • Author(s)
      山下ユキコ, 合田圭吾, 大坪忠宗, 和中敬子, 津田裕子, 手納直規
    • Organizer
      第33回メディシナルケミストリーシンポジウム
    • Place of Presentation
      幕張国際研修センター
    • Year and Date
      2015-11-25
    • Related Report
      2015 Annual Research Report
  • [Presentation] Design of plasmin inhibitors targeting the S1’subsite2015

    • Author(s)
      M. Kusano, K. Hidaka, K. Gohda, N. Teno, K. Wanaka, Y. Tsuda
    • Organizer
      The 52nd Japanese Peptide Symposium
    • Place of Presentation
      Hiratsuka
    • Year and Date
      2015-11-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Structural studies on plasminogen activation and plasmin inhibition.2015

    • Author(s)
      R.H.P. Law, A.J. Quek, G. Wu, P.J. Conroy, K Hidaka, T. T. Caradoc-Davies, Y Tsuda, J. C. Whisstock
    • Organizer
      The 9th General Meeting of International Proteolysis Society
    • Place of Presentation
      Peneng, Malysia
    • Year and Date
      2015-10-04
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The x-ray crystal structure of microplasmin with a small-molecular active site inhibitor PSI-112.2015

    • Author(s)
      G. Wu, K. Hidaka, D. Jeevarajah, Y. Tsuda, J. C Whisstock, R.H.P. Law
    • Organizer
      The 9th General Meeting of International Proteolysis Society
    • Place of Presentation
      Peneng, Malysia
    • Year and Date
      2015-10-04
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 活性中心指向型プラスミン阻害剤の長鎖P1'残基導入による構造活性相関2015

    • Author(s)
      草野真衣、日高興士、合田圭吾、手納直規、和中敬子、津田裕子
    • Organizer
      第20回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-08-21
    • Related Report
      2015 Annual Research Report
  • [Presentation] Study on the plasmin inhibitors: Replacement of the P2 and P1’ residues2014

    • Author(s)
      Ayako Suzuki, Koushi Hidaka, Keigo Gohda, Naoki Teno, Keiko Wanaka and Yuko Tsuda
    • Organizer
      The 51st Japanese Peptide Symposium
    • Place of Presentation
      徳島
    • Year and Date
      2014-10-22 – 2014-10-24
    • Related Report
      2014 Research-status Report
  • [Presentation] Development of active center-directed plasmin inhibitors2014

    • Author(s)
      Yoshio Okada, Keiko Wanaka, Yuko Tsuda
    • Organizer
      15th Akabori Conference/Japanese-German Symposium on Peptide Science
    • Place of Presentation
      Boppard, Germany
    • Year and Date
      2014-09-07 – 2014-09-10
    • Related Report
      2014 Research-status Report
  • [Presentation] Plasmin specific inhibitors: Additional interaction at the S2/S3 and S’1 sites2014

    • Author(s)
      Yuko Tsuda, Koushi Hidaka, Keigo Gohda, Naoki Teno, Keiko Wanaka
    • Organizer
      33rd European Peptide Symposium
    • Place of Presentation
      Sofia, Bulgaria
    • Year and Date
      2014-08-31 – 2014-09-05
    • Related Report
      2014 Research-status Report
  • [Presentation] プラスミン(PL)選択的阻害剤を目指して~P1’残基の構造変換2014

    • Author(s)
      前原いつか、松井千紗、村上弥生、日高興士、合田圭吾、手納直規、和中敬子、津田裕子
    • Organizer
      第19回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      吹田、千里ライフサイエンスセンター
    • Year and Date
      2014-08-08 – 2014-08-09
    • Related Report
      2014 Research-status Report
  • [Presentation] P2残基置換によるプラスミン阻害剤の構造活性相関2014

    • Author(s)
      渥美沙紀、松井千紗、日高興士、合田圭吾、手納直規、和中敬子、津田裕子
    • Organizer
      日本薬学会134年会
    • Place of Presentation
      熊本、熊本市総合体育館その他
    • Related Report
      2013 Research-status Report
  • [Presentation] プラスミン(PL)選択的阻害剤を目指して~結合ポケットの比較からデザインする2013

    • Author(s)
      岡部未奈子、日高興士、合田圭吾、手納直規、和中敬子、津田裕子
    • Organizer
      第18回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      吹田、千里ライフサイエンスセンター
    • Related Report
      2013 Research-status Report
  • [Presentation] 活性中心志向型プラスミン阻害剤の探索2013

    • Author(s)
      津田裕子
    • Organizer
      生命分子機能研究会2013学術集会
    • Place of Presentation
      長浜、長浜バイオ大学
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Search for plasmin specific inhibitors: Extension on the P2 residue2013

    • Author(s)
      Atsumi S, Hidaka K, Gohda K, Teno N, Wanaka K, Tsuda Y
    • Organizer
      4th Asia-Pacific International Peptide Symposium/50th Japanese Peptide Symposium
    • Place of Presentation
      吹田、ホテル阪急エキスポパーク
    • Related Report
      2013 Research-status Report
  • [Remarks] 教員総覧

    • Related Report
      2015 Annual Research Report
  • [Remarks] 教員総覧

    • Related Report
      2014 Research-status Report
  • [Remarks] 教員総覧

    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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