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The development of activators of cellular fibrinolysis

Research Project

Project/Area Number 10559008
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field 広領域
Research InstitutionTokyo Noko University Tokyo University of Agriculture and Technology

Principal Investigator

HASUMI Keiji  Tokyo University of Agriculture and Technology, Faculty of Agriculture, Associate Professor, 農学部, 助教授 (20208474)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Kazunori  Torii Pharmaceutical Co., Research Laboratory, Senior Investigator, 研究所, 研究室長(研究者職)
KITANO Yoshikazu  Tokyo University of Agriculture and Technology, Faculty of Agriculture, Assistant Professor, 農学部, 助手 (10302910)
CHIBA Kazuhiro  Tokyo University of Agriculture and Technology, Faculty of Agriculture, Associate Professor, 農学部, 助教授 (20227325)
UCHIYAMA Hiroyuki  Torii Pharmaceutical Co., Research Laboratory, Investigator, 研究所, 研究員
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥4,000,000 (Direct Cost: ¥4,000,000)
KeywordsCyclic peptides / Fibrinolysis / Prothrombin / Blood coagulation / PHBP / prothrombin / 環状ペピチド / 組溶系
Research Abstract

The mechanism of plactin action : Two plasma factors that are essential for plactin-mediated prourokinase activation were identified by using plactin-Sepharose affinity chromatography. One was prothrombin, a coagulation factor, and the other was plasma hyaluronan binding protein(PHBP), a plasma serine protease with unknown physiological function. Plactin bound to prothrombin in a cooperative manner. The binding caused conformational change of the prothrombin molecule and modulated prothrombin activation by coagulation factor Xa. Prothrombinase-catalyzed prothrombin activation was inhibited, while activation by non-prothrombinase factor Xa was markedly enhanced. In the incubation of U937 cells with human plasma, the activation of prothrombin to thrombin was increased by plactin. The resulting thrombin cleaved prourokinase at Agr^<156>-Phe^<157>, yielding inactive two-chain urokinase(thrombin-cleaved urokinase ; tc-uPA/T). This urokinase species was activated to two-chain urokinase by cy … More statin-sensitive peptidase of U937 cells. In the presence of plactin, PHBP activated cellular benzamidine-sensitive protease, which in turn activated prourokinase on U937 cells. Thus, plactin enhances cellular fibrinolytic activity via two mechanisms, the prothrombin pathway and the PHBP pathway.
Pharmacological evaluation of plactin and its derivatives : We obtained following results evaluating 〜80 plactin derivatives. (1)Cyclotetrapeptide derivatives have comparable activity as compared with cyclopentapeptides. (2)Activity of cyclopeptides is dependent on one Lys or Agr and three to four hydrophobic residues. (3)Partial elimination of amido bond can retain activity, while solubility and bioavailability of the molecule are not improved. Plactin and one of its derivative with reduced amido bond were stable in plasma, and their half-life of these compounds in the circulation was >30 min, while these were not active when administered orally or intraperitoneally. In the thrombin-induced pulmonary embolism model mouse, these compounds showed prominent effects at an intravenous dose of 0.1 mg/kg. These results may partly be explained by the dual action of plactin, anticoagulation and fibrinolytic activation.
Development of chemical synthetic methods that are applicable to the synthesis of plactin derivatives : Several electrolytic oxidation/reduction conditions were tested to improve organic synthetic specificity and yield. Some conditions established were applicable to the modification of peptide compounds including plactins.
Identification of compounds that enhance fibrinolysis and/or suppress atherosclerosis : We identified several compounds with activity to enhance the fibrinolytic system and suppress pathways leading to formation of atherosclerosis. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (51 results)

All Other

All Publications (51 results)

  • [Publications] Hasumi, K.: "Isolation of SMTP-3, -4, -5 and-6, novel analogs of staplabin, and their effects on plasminogen activation and fibrinolysis."J. Antibiotics. 51. 1059-1068 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sekiyama, Y.: "Biosynthesis of acaterin : incorporation of glycerol into the C3 branched unit."Tetrahedron Lett.. 39. 6233-6236 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Harada, T.: "Induction of low density lipoprotein catabolism by a fungal sesquiterpene ester, FR111142."Biochem. Biophys. Res. Commun.. 251. 830-834 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shinonara, C.: "11-Keto-9 (E), 12 (E)-octadecadienoic acid, a novel fatty acid that enhances fibrinolytic activity of endothelial cells."J. Antibiotics. 52. 171-174 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K.: "Stereoselective Diels-Alder Reaction of Electrogenerated Quinones using PTEF-fiber Coated Electrode"Tetrahedron Lett.. 39. 5527-5530 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K.: "Synthesis of Chromans by Photosensitized Electrochemical Oxidation of Sulfides Mediated by Methylene Blue"Tetrahedron Lett.. 39. 9035-903* (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sekiyama, Y.: "Biosynthesis of acaterin : metabolic fate of sn-3 hydrogens of glycerol during the formation of 4-dehydroacaterin."Tetrahedron Lett.. 40. 4223-4226 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikanishi, T.: "Inhibition of plasminogen activator inhibitor-1 by 11-keto-9 (E), 12 (E)-octadecadienojc acid, a novel aftty acid produced by Trichodema sp.."J. Antibiot.. 52. 797-802 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hu, W.: "Activation of fibrinolysis by SMTP-7 and -8, novel staplabin analogs with a pseudosymmetric structure."J. Antibiot.. 53. 241-247 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shinohara, C.: "Enhancement of fibrinolytic activity of vascular endothelial cells by chaetoglobosin A, crinipellin B, geodin and triticone B."J. Antibiot.. 53. 262-268 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Jinno, M.: "Electrochemical generation and reaction of o-Quinodimethanes from {[[2-(2, 2-dibutyl-2-stannahexyl)phenyl]methyl]thio} benzenes."Org. Lett.. 1. 435-438 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K.: "Dihydrobenzofuran synthesis by an anodic [3+2] cycloaddition of phenols and unactivated alkenes."J. Org. Chem.. 64. 7654-7656 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Luo, T.: "Human immunodeficiency virus type 1 Nef-induced CD4 cell surface downregulation is inhibited by a novel antibiotic."J. Virol.. 75. 2488-2492 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K.: "Benzylic Intermolecular Carbon-Carbon Bond Formation by Selective Anodic Oxidation of Dithioacetals"Org. Lett.. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kim, S.: "Benzylic Nitroalkylation by Paired Electrolysis of Benzyl Sulfides in Nitroalkanes"J. Electroanal. Chem.. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K.: "A Perfluorinated Micellar Reaction System in Lithium Perchlorate/Acetonitrile ; Enhanced Efficiency in Anodic Electron-Transfer and Intermolecular Cycloaddition"Electrochem. Commun.. 3. 63-66 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kim, S.: "Alkylindan Synthesis via an Intermolecular [3+2] Cycloaddition between Unactivated Alkenes and in situ generated p-Quinomethanes"Tetrahedron Lett.. 41. 7079-7083 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Luo, T., Fredericksen, B.L., Hasumi, K., Endo, A.and Garcia, J.V.: "Human immunodeficiency virus type 1 Nef-induced CD4 cell surface downregulation is inhibited by a novel antibiotic."J.Virol.. 75. 2488-2492 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hu, W., Ohyama, S.and Hasumi, K.Activation of fibrinolysis by SMTP-7 and -8, novel staplabin analogs with a pseudosymmetric structure.: J.Antibiotics. 53. 241-247 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shinohara, C., Chikanishi, T., Nakashima, S., Hashimoto, A., Hamanaka, A., Endo, A.and Hasumi, K.: "Enhancement of fibrinolytic activity of vascular endothelial cells by chaetoglobosin A, crinipellin B, geodin and triticone B."J.Antibiotics. 53. 262-268 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shinohara, C., Hasumi, K., Chikanishi, T., Kikuchi, T.and Endo, A.: "11-Keto-9(E), 12(E)-octadecadienoic acid, a novel fatty acid that enhances fibrinolytic activity of endothelial cells."J.Antibiotics. 52. 171-174 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sekiyama, Y., Fujimoto, Y., Hasumi, K.and Endo, A.: "Biosynthesis of acaterin : metabolic fate of sn-3 hydrogens of glycerol during the formation of 4-dehydroacaterin."Teterahedron Lett.. 40. 4223-4226 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikanishi, T., Shinohara, C., Kikuchi, T., Endo, A.and Hasumi, K.: "Inhibition of plasminogen activator inhibitor-1 by 11-keto-9(E), 12(E)-octadecadienoic acid, a novel fatty acid produced by trichoderma sp.."J.Antibiotics. 52. 797-802 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sekiyama, Y., Araya, H., Hasumi, K., Endo, A.and Fujimoto, Y.: "Biosynthesis of acaterin : incorporation of glycerol into the C3 branched unit."Tetrahedron Lett.. 39. 6233-6236 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Harada, T., Hasumi, K.and Endo, A.: "Induction of low density lipoprotein catabolism by a fungal sesquiterpene ester, FR111142."Biochem.Biophys. Res.Commun.. 251. 830-834 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hasumi, K., Ohyama, S., Kohyama, T., Ohsaki, Y., Takayasu, R.and Endo, A.: "Isolation of SMTP-3, -4, -5 and -6, novel analogs of staplabin, and their effects on plasminogen activation and fibrinolysis."J.Antibiotics. 51. 1059-1068 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K. ; Uchiyama, R. ; Kim, S. ; Kitano, Y. ; Tada, M.: "Benzylic Intermolecular Carbon-Carbon Bond Formation by Selective Anodic Oxidation of Dithioacetais"Org.Lett.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kim, S. ; Kitano, Y. ; Tada, M. ; Chiba, K.: "Benzylic Nitroalkylation by Paired Electrolysis of Benzyl Sulfides in Nitroalkanes"J.Electroanal.Chem.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K. ; Kono Y. ; Kitayama, M. ; Uchiyama, R. ; Kim, S. ; Kitano, Y. ; Tada, M.: "A Perfluorinated Micellar Reaction System In Lithium Perchlorate/Acetonitrile ; Enhanced Efficiency in Anodic Electron-Transfer and Intermolecular Cycloaddition."Electrochemistry Communications. 3. 63-66 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kim, S. ; Kitano, Y. ; Tada, M. ; Chiba, K.: "Alkylindan Synthesis via an Intermolecular[3+2]Cycloaddition between Unactivated Alkenes and in situ generated p-Quinomethanes"Tetrahedron Letters. 41. 7079-7083 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K. ; Fukuda, M. ; Kim, S. ; Kitano, Y. ; Tada, M.: "Dihydrobenzofuran Synthesis by an Anodic[3+2]Cycloaddition of Phenois and Unactivated Alkenes"J.Org.Chem.. 64. 7654-7656 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Jinno, M. ; Kitano, Y. ; Tada, M. ; Chiba, K.: "Electrochemical Generation and Reaction of o-Quinodimethanes from{[[2-(2, 2-Dibutyl-2-stannahexyl)phenyl]methyl]thio}benzens"Org.Lett.. 1. 435-8 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K. ; Yamaguchi, Y. ; Tada, M.: "Synthesis of Chromans by Photo-sensitized Electrochemical Oxidation of Sulfides Mediated by Methylene Blue"Tetrahedron Lett.. 39. 9035-9038 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chiba, K. ; Jinno, M. ; Kuramoto, R. ; Tada, M.: "Stereoselective Diels-Alder Reaction of Electrogenerated Quinones using PTFE-fiber Coated Electrode"Tetrahedron Lett.. 39. 5527-5530 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Luo,T.: "Human immunodeficiency virus type 1 Nef-induced CD4 cell surface downregulation is inhibited by a novel antibiotic."J.Virol.. 75. 2488-2492 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chiba,K.: "Benzylic Intermolecular Carbon-Carbon Bond Formation by Selective Anodic Oxidation of Dithioacetals"Org.Lett.. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kim,S.: "Benzylic Nitroalkylation by Paired Electrolysis of Benzyl Sulfides in Nitroalkanes"J.Electroanal.Chem.. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chiba,K.: "A Perfluorinated Micellar Reaction System In Lithium Perchlorate/Acetonitrile ; Enhanced Efficiency in Anodic Electron-Transfer and Intermolecular Cycloaddition"Electrochem.Commun.. 3. 63-66 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kim,S.: "Alkylindan Synthesis via an Intermolecular [3+2] Cycloaddition between Unactivated Alkenes and in situ generated p-Quinomethanes"Tetrahedron Lett.. 41. 7079-7083 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sekiyama, Y.: "Biosynthesis of acaterin: metabolic fate of sn-3 hydrogens of glycerol during the formation of 4-dehydroacaterin."Tetrahedron Lett.. 40. 4223-4226 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chikanishi, T.: "Inhibition of plasminogen activator inhibitor-1 by 11-keto-9(E), 12(E)-octadecadienoic acid, a novel fatty acid produced by Trichoderma sp.."J. Antibiot.. 52. 797-802 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hu, W.: "Activation of fibrinolysis by SMTP-7 and -8, novel staplabin analogs with a pseudosymmetric structure."J. Antibiot.. 53(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shinohara, C.: "Enhancement of fibrinolytic activity of vascular endothelial cells by chaetoglobosin A, crinipellin B, geodin and triticone B."J. Antibiot.. 53(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Jinno, M.: "Electrochemical generation and reaction of o-Quinodimethanes from {[[2- (2,2-dibutyl-2-stannahexyl)phenyl]methyl]thio}benzenes."Org. Lett.. 1. 435-438 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chiba, K.: "Dihydrobenzofuran synthesis by an anodic [3+2] cycloaddition of phenols and unactivated alkenes."J. Org. Chem.. 64. 7654-7656 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hasumi,K.: "Isolation of SMTP-3,-4,-5 and -6,novel analogs of staplabin,and their effects on plasminogen activation and fibrinolysis." J.Antibiotics. 51. 1059-1068 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sekiyama,Y.: "Biosynthesis of acaterin: incorporation of glycerol into the C3 branched unit." Tetrahedron Lett.39. 6233-6236 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Harada,T.: "Induction of low density lipoprotein catabolism by a fungal sesquiterpene ester,FR111142." Biochem.Biophys.Res.Commun.251. 830-834 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shinonara,C.: "11-Keto-9(E).12(E)-octadecadienoic acid,a novel fatty acid that enhances fibrinolytic activity of endothelial cells." J.Antibiotics. 52. 171-174 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chiba,K.: "Stereoselective Diels-Alder Reaction of Electrogenerated Quinones using PTFE-fiber Coated Electrode" Tetrahedron Lett.39. 5527-5530 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chiba,K.: "Synthesis of Chromans by Photosensitized Electrochemical Oxidation of Sulfides Mediated by Methylene Blue" Tetrahedron Lett.39. 9035-9038 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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