2006 Fiscal Year Final Research Report Summary
Structure-based drug designs for the treatment of prion disease
| Project/Area Number |
16209017
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Virology
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| Research Institution | Nagasaki University |
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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)
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| 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)
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| Project Period (FY) |
2004 – 2006
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| Keywords | prion diseases / prion strain / conformation / NMR / drug discovery |
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| 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.
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[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:
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Journal Title
Histochem Cell Biol. 127 (3)
Pages: 291-301
Description
「研究成果報告書概要(欧文)」より
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