Design of the active site-directed plasmin inhibitor oriented to the clinical applications
| Project/Area Number |
16K08333
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Kobe Gakuin University |
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Principal Investigator |
Tsuda Yuko 神戸学院大学, 薬学部, 教授 (10098478)
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| Co-Investigator(Kenkyū-buntansha) |
北條 恵子 神戸学院大学, 薬学部, 助教 (20289028)
日高 興士 神戸学院大学, 薬学部, 講師 (30445960)
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| Research Collaborator |
TENO naoki 広島国際大学, 医療栄養学部, 教授 (00535586)
GOHDA keigo 関西分子設計研究会, 主席研究員
WANAKA keiko 血栓止血研究プロジェクト, 主席研究員
HATTORI kouichi 順天堂大学, 医学部, 教授 (10360116)
LAW ruby モナッシュ大学, Department of Biochemistry and Molecular Biology, 講師
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 活性中心指向型 / 炎症性疾患治療薬 / プラスミン阻害剤 / 分子設計 / 活性部位指向型 / 阻害剤 / プラスミン / P1’ 残基 / 臨床応用 |
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| Outline of Final Research Achievements |
Plasmin (Plm), a trypsin like protease, is involved in the fibrinolysis pathway. Additionally, the action of Plm at the specific regions of the extracellular milieu lead to the digestion of many proteins at the localized cell surface that results in inducing cell inversion and metastasis and alternating the expression of cytokines. A growing body of data suggests that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent as well as for hemostatics.
In this work, we developed a new Plm inhibitor that has 2.4 fold higher Plm inhibition (IC50 = 0.22 microM) as well as selectivity (Plm/urokinase) by 35-fold, compared with YO-2 (original Plm inhibitor, IC50 = 0.53 microM). And we presented the efficiency of Plm inhibitor, YO-2, which reduced tissue damage and improved inflammation-associated lethality in a murine fulminant MAS model.
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| Academic Significance and Societal Importance of the Research Achievements |
Plmの血栓以外のタンパク質を分解する活性を制御することを目的として、Plm阻害剤を探索した。
Plmの活性化がサイトカインの遊離を誘導し、炎症発症を引き起こす経路を示し、Plm阻害剤をMAS病態マウスに投与して、MASにおける致死率を低下させることを示した。トラネキサム酸（Tra）はリシン結合部位(LBS）に結合することによりPlmを阻害し、安全性が高いので止血薬として現在も臨床現場で汎用されている。著者らが開発した活性中心指向型Plm阻害剤の分子内のTraは、Plmの活性中心に結合しており、単独のTraとは作用点が異なる。新しいPlm阻害剤開発のアプローチといえる。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] X-ray crystal structure of plasmin with tranexamic acid-derived active site inhibitors.2017
Author(s)
Law RHP, Wu G, Leung EWW, Hidaka K, Quek AJ, Caradoc-Davies TT, Jeevarajah D, Conroy PJ, Kirby NM, Norton RS, Tsuda Y, Whisstock JC.
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Journal Title
Blood Adv.
Volume: 1
Issue: 12
Pages: 766-771
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome2017
Author(s)
1.Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonser S, Ohta Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B and Hattori K
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Journal Title
Blood
Volume: 印刷中
Issue: 1
Pages: 59-72
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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