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

• Project/Area Number: 25460164
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kobe 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: ¥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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Study on the plasmin inhibitors: Replacement of the P2 and P1’ residues (2015)
  • Author(s): Suzuki A, Hidaka K, Gohda K, Teno N, Wanaka K, Tsuda Y.
  • Journal Title: Peptide Science 2014 Volume: 2015 Pages: 209-210
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthetic substrates specific to activated plasmin can monitor the enzymatic functional status in situ in breast cancer cells (2014)
  • 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
  • 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
  • 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
• [Presentation] Active site directed plasmin inhibitors: modification on P1’ residue (2015)
  • 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
  • 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
• [Presentation] Design of plasmin inhibitors targeting the S1’subsite (2015)
  • 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
• [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
  • 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
  • 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
• [Presentation] Study on the plasmin inhibitors: Replacement of the P2 and P1’ residues (2014)
  • 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
• [Presentation] Development of active center-directed plasmin inhibitors (2014)
  • 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
• [Presentation] Plasmin specific inhibitors: Additional interaction at the S2/S3 and S’1 sites (2014)
  • 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
• [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
• [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
• [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
• [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
  • Invited
• [Presentation] Search for plasmin specific inhibitors: Extension on the P2 residue (2013)
  • 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
• [Remarks] 教員総覧
• [Remarks] 教員総覧
• [Remarks] 教員総覧