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Screening for inhibitors of Cholesteryl Ester Transfer Protein

Research Project

Project/Area Number 09480147
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionThe Kitasato Institute

Principal Investigator

TOMODA Hiroshi  Research Center for Biological Function, The Kitasato Institute, Director, 生物機能研究所, 副所長 (70164043)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Yoko  Research Center for Biological Function, The Kitasato Institute, Chief Researcher, 生物機能研究所, 室長 (80197186)
TABATA Noriko  Research Center for Biological Function, The Kitasato Institute, Researcher, 生物機能研究所, 研究員 (60260080)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1999: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsCETP / inhibitor / microbial origin / cholesteryl ester / Ferroverdin / Erabulenol / Pyripyropene誘導体 / 放射菌代謝産物 / エラブレノール / 糸状菌代謝産物
Research Abstract

Cholesteryl ester transfer protein (CETP) promotes exchange and transfer of neutral lipids such as cholesteryl ester (CE) and TG between plasma lipoproteins. Evidence has been accumulating of the importance of CETP in atherosclerosis. Therefore, inhibition of CETP is proposed as a novel target for anti-atherosclerotic drugs. Interestingly, the mechanism of CETP-mediated lipid transfer is still unclear. In fact, small molecules modulating the CETP activity have been searched for extensively for therapeutic and biochemical purposes.
Over twenty thousand samples of microbial culture broths were subjected to our screening program for CETP inhibitors. Finally, we discovered erabulenols from a fungal strain, and ferroverdins from an actinomycete strain, as novel CETP inhibitors. We also observed that known fungal metabolites, sclerotiorin originally isolated as a yellow pigment and L681512 compounds isolated as elastase inhibitors, inhibit CETP activity.
From the model reaction, sclerotiorin can react with a primary amine such as N-terminal cysteine and/or lysines in CETP molecule to form a covalent bond. Among CETP inhibitors of natural origin ferroverdin B show very potent CETP inhibition with a nanomolar ICィイD250ィエD2 value. Ex vivo efficacy was shown using transgenic mice for sclerotiorin and L681512.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] H. Tomoda, N. Tabata, R. Masuma, et al.: "Erabulenols A and B, inhibitors cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. I.. Production, isolation and biological properties"J. Antibiot. 51. 618-623 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N. Tabata, H. Tomoda, and S. Omura: "Erabulenols A and B, inhibitors cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II.Structure elucidation of erabulenols A and B"J. Antibiot. 51. 624-628 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Tomoda, C. Matsushima, N. Tabata, I. Namatame, et al.: "Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones"J. Antibiot. 52. 160-170 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N. Tabata, Htomoda, Y. Yamaguchi, R, Masuma, et al.: "Inhibition of cholesreryl ester transfer protein by fungal metabolites, L681, 512"J. Antibiot. 52. 1042-1045 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Tomoda, N. Tabata, M . shinose, Y. Takahashi, H. et al.: "Ferroverdins, Inhibitors of cholesreryl ester transfer protein produced by Streptomyces sp. WK-5344. II.. Structure elucidation"J. Antibiot. 52. 1101-1107 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N. Tabata, H. Tomoda, and S. Omura: "Ferroverdins, Inhibitors of cholesreryl ester transfer protein produced by Streptomyces sp. WK-5344. II.. Structure elucidation"J. Antibiot. 52. 1108-1113 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Tomoda, N.Tabata, R.Masuma, S.-Y.Si, and S.Omura: "Erabulenols A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. I. Production, isolation and biological properties"J. Anitibiot.. 51. 618-623 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N.Tabata, H.Tomoda, and S.Omura: "Erabulenoles A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II. Structure elucidation of erabulenols A and B"J. Anitibiot.. 51. 624-628 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Tomoda, C.Matsushima, N.Tabata, I.Namatame, H.Tanaka, M.J.Bamberger, H.Arai, M.Fukazawa, K.Inoue, and S.Omura: "Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones"J. Anitibiot.. 52. 160-170 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N.Tabata, H.Tomoda, Y.Yamaguchi, R.Masuma, M.J.Bamberger, and S.Omura: "Inhibition of cholesteryl ester transfer protein by fungal metabolites"J. Anitibiot.. 52. 1042-1045 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Tomoda, N.Tabata, M.Shinose, Y.Takahashi, H.B.Woodruff, and S.Omura: "Ferroverdins, Inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp. WK-5344. I. Production, isolation and biological properties"J. Anitibiot.. 52. 1101-1107 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N.Tabata, H.Tomoda, and S.Omura: "Ferroverdins, Inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp. WK-5344. II. Structure elucidation"J. Anitibiot.. 52. 1108-1113 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Tomoda,C.Matsushima,N.Tabata,I.Namatame: "Structure-specific inhibition of cholesreryl ester transfer protein by azaphilones"J.Antibiot.. 52. 160-170 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] N.Tabata,H.Tomoda,Y.Yamaguchi,R.Masuma: "Inhibition of cholesteryl ester transfer protein by fungal metabolites, L681.512"J.Antibiot.. 52. 1042-1045 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Tomoda,N.Tabata,M.Shinose,Y.Takahashi: "Ferroverdins, Inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp.WK-5344.I.Production, isolation and biological properties"J.Antibiot.. 52. 1101-1107 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] N.Tabata, H.Tomoda,S.Omura: "Ferroverdins, Inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp.WK-5344.II.Structure elucidation"J.Antibiot.. 52. 1108-1113 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tomoda,H., Tabata,N., et al.: "Erabulenoles A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. I. Production, isolation and biological properties." J.Antibiot. 51. 618-623 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomoda,H., Tabata,N., et al.: "Erabulenoles A and B, inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp. FO-5637. II. Structure elucidation of erabulenoles A and B" J.Antibiot. 51. 624-628 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomoda,H., Tabata,N., et al.: "Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones." J.Antibiot. 52. 160-170 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiroshi Tomoda, Noriko Tabata et.al.,: "Erabulenoles A and B,inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp.FO-5637.I.Production,isolation and biological properties." J.Antibiotics. 51(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Noriko Tabata, Hiroshi Tomoda et.al.,: "Erabulenoles A and B,inhibitors of cholesteryl ester transfer protein, produced by Penicillium sp.FO-5637.II.Structure elucidation of erabulenoles A and B." J.Antibiotics. 51(印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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

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