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2006 Fiscal Year Final Research Report Summary

Structure-based drug designs for the treatment of prion disease

Research Project

Project/Area Number 16209017
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Virology
Research InstitutionNagasaki University

Principal Investigator

KATAMINE Shigeru  Nagasaki University, Graduate School of Biomedical Sciences, Department of Microbiology and Immunology, Professor, 大学院医歯薬学総合研究科, 教授 (40161062)

Co-Investigator(Kenkyū-buntansha) ITO Takasi  Nagasaki University, Department of Microbiology and Immunology, Professor, 大学院医歯薬学総合研究科, 教授 (90306275)
NISHIDA Noriyuki  Nagasaki University, Graduate School of Biomedical Sciences, Department of Microbiology and Immunology, Assistant Professor, 大学院医歯薬学総合研究科, 助教授 (40333520)
KUWATA Kazuo  Gifu University, Center for Emerging Infectious Diseases, 人獣感染防御研究センター, 教授 (00170142)
Project Period (FY) 2004 – 2006
Keywordsprion diseases / prion strain / conformation / NMR / drug discovery
Research Abstract

The conversion of the normal form of prion protein (PrP^c) to a disease-associated form (PrP^<Sc>) is a key molecular event in the pathogenesis of Transmissible Spongiform Encephalopathies (TSEs). We conducted a computed screening of ligands which can bind to mouse prion, particularly to the fourteen amino acids surrounding a pocket located in the helix A-S2 loop and the C-terminal half of helix B, which are structurally less stable shown by the CPMG dispersion relaxation measurement and high-pressure NMR. From over 320,000 substances, 59 candidates were selected and subjected to ex vivo tests. Among the 14 commercially-available compounds tested, of which one efficiently reduced PrP^<Sc> production in human TSE-infected cell culture (1.3 μM IC_<50>). Thermal unfolding experiments showed that the ellipticity of recombinant mouse PrP^c remains unchanged at around 40℃ in the presence of the compound, suggesting that the PrP^c conformation was significantly stabilized. Application of this new strategy, which we have designated 'Dynamics-Based Drug-Design', not only provides new insight in the molecular mechanism of PrP^<Sc> production, but may also lead the way to the development of drugs for TSEs.

  • Research Products

    (12 results)

All 2007 2006

All Journal Article (11 results) Book (1 results)

  • [Journal Article] Newly established in vitro system with fluorescent proteins shows that abnormal expression of downstream prion protein-like protein in mice is probably due to functional disconnection between splicing and 3' formation of prion protein pre-mRNA.2007

    • Author(s)
      Yoshikawa D et al.
    • Journal Title

      Gene 386 (1-2)

      Pages: 139-146

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Immunization with recombinant bovine but not mouse prion protein delays the onset of disease in mice inoculated with a mouse-adapted prion.2007

    • Author(s)
      Ishibashi D etal
    • Journal Title

      Vaccine 25(6)

      Pages: 985-992

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.2007

    • Author(s)
      Miyazawa K et al.
    • Journal Title

      Histochem Cell Biol 127(3)

      Pages: 291-301

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Newly established in vitro system with fluorescent proteins shows that 3 abnormal expression of downstream prion protein -like protein in mice is probably due to functional disconnection between splicing and 3' formation of prion protein pre-mRNA2007

    • Author(s)
      Yoshikawa D, Kopacek J, Yamaguchi N, Ishibashi D, Yamanaka H, Yamaguchi Y, Katamine S, Sakaguchi S
    • Journal Title

      Gene 386

      Pages: 139-146

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Immunization with recombinant bovine but not mouse prion protein delays the onset of disease in mice inoculated with a mouse-adapted prion.2007

    • Author(s)
      Ishibashi D, Yamanaka H, Yamaguchi N, Yoshikawa D, Nakamura R, Okimura N, Yamaguchi Y, Shigematsu K, Katamine S, Sakaguchi S
    • Journal Title

      Vaccine 25 (6)

      Pages: 985-992

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.2007

    • Author(s)
      Miyazawa K, Kanaya T, Tanaka S, Takakura I, Watanabe K, Ohwada S, Kitazawa H, Rose MT, Sakaguchi S, K, Ohwada S, Kitazawa H, Rose MT, Sakaguchi S, Katamine S, Yamaguchi T, Aso H:
    • Journal Title

      Histochem Cell Biol. 127 (3)

      Pages: 291-301

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Prion strain-dependent differences in conversion of mutant prion proteins in cell culture.2006

    • Author(s)
      Atarashi R et al.
    • Journal Title

      J Virol 80 (16)

      Pages: 7854-7862

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies.2006

    • Author(s)
      Ishikawa K etal
    • Journal Title

      J Neurochem 99(1)

      Pages: 198-205

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] プリオン仮説(タンパク質単独犯説)は本当か。2006

    • Author(s)
      片峰 茂
    • Journal Title

      科学(岩波書店) 11月号

      Pages: 1122-1126

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Prion strain-dependent differences in conversion of mutant prion proteins in cell culture.2006

    • Author(s)
      Atarashi R, Sim VL, Nishida N, Caughey B, Katamine S
    • Journal Title

      J Virol 80 (16)

      Pages: 7854-7862

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies.2006

    • Author(s)
      Ishikawa K et al.
    • Journal Title

      J Neurochem 99(1)

      Pages: 198-205

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] 論理的創薬入門-構造生物学に基づくアプローチ2006

    • Author(s)
      桑田 一夫
    • Total Pages
      276
    • Publisher
      共立出版
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2008-05-27  

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