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Molecular Design of Drugs recognizing Trinucleotide Repeat Sequence.

Research Project

Project/Area Number 15201042
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied genomics
Research InstitutionOsaka University (2005)
Kyoto University (2003-2004)

Principal Investigator

NAKATANI Kazuhiko  Osaka University, The Institute of Scientific and Industrial Research, Professor, 産業科学研究所, 教授 (70237303)

Co-Investigator(Kenkyū-buntansha) ZHOU Da-Yang  Osaka University, The Institute of Scientific and Industrial Research, Research Associate, 産業科学研究所, 助手 (00324848)
HAGIHARA Masaki  Osaka University, The Institute of Scientific and Industrial Research, Research Associate, 産業科学研究所, 助手 (40403000)
TAKEI Fumie  Osaka University, The Institute of Scientific and Industrial Research, Technical Staff, 産業科学研究所, 教務職員 (30252711)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥50,180,000 (Direct Cost: ¥38,600,000、Indirect Cost: ¥11,580,000)
Fiscal Year 2005: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2004: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
Fiscal Year 2003: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
KeywordsTrinucleotide Repeat / Genetic Disease / ミスマッチ / CAGリピート
Research Abstract

DNA trinucleotide repeats, particularly CXG, are common within the human genome. However, expansion of trinucleotide repeats is associated with a number of disorders, including Huntington's disease, spinobulbar muscular atrophy, and spinocerebellar ataxia1-4. In these cases, the repeat length is known to correlate with decreased age of onset and disease severity5,6. Repeat expansion of (CAG)n, (CTG)n, and (CGG)n trinucleotides may be related to the increased stability of alternative DNA hairpin structures consisting of CXG/CXG triads with X-X mismatches7-11. Small molecule ligands that selectively bound to CAG repeats could provide an important probe for determining repeat length and an important tool for investigating the in vivo repeat extension mechanism. Here we report that naphthyridine-azaquinolone (NA,1) is a ligand for CAG repeats and can be used as a diagnostic tool for determining repeat length. We show by NMR spectroscopy that binding of NA to CAG repeats induces extrusion of a cytidine nucleotide from the DNA helix.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (12 results)

All 2005 2004 Other

All Journal Article (7 results) Publications (5 results)

  • [Journal Article] Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats2005

    • Author(s)
      K.Nakatani, C.Kojima et al.
    • Journal Title

      Nature Chemical Biology 1・1

      Pages: 43-43

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats,2005

    • Author(s)
      K.Nakatani, C.Kojima et al.
    • Journal Title

      Nature Chemical Biology 1(1)

      Pages: 43-43

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A new ligand binding to G-G mismatch having improved thermal and alkaline stability2005

    • Author(s)
      中谷和彦ほか
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters 15

      Pages: 259-262

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Highly Sensitive Detection of GG Mismatched DNA by Surfaces Immobilized Naphthyridine Dimer through Poly (ethylene oxide) Linkers2004

    • Author(s)
      中谷和彦ほか
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters 14

      Pages: 1105-1108

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Solvent Effects on the Suppression of Oxidative Decomposition of Guanine by Phenyl Group Attachment in DNA2004

    • Author(s)
      中谷和彦ほか
    • Journal Title

      Journal of Physical Chemistry, B 108

      Pages: 7500-7505

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The binding of Guanine-Guanine Mismatched DNA to Naphthyridine Dimer Immobilized Sensor Surfaces : Kinetic Aspects2004

    • Author(s)
      中谷和彦ほか
    • Journal Title

      Bioorganic & Medicinal Chemistry 12

      Pages: 3117-3123

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 2-Ureidoquinoline : a useful molecular element for stabilizing single cytosine ant thymine bulges2004

    • Author(s)
      中谷和彦ほか
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters 14

      Pages: 3431-3433

    • Related Report
      2004 Annual Research Report
  • [Publications] 中谷和彦ほか: "Induction of a Remarkable Conformational Change in a Human Telomeric Sequence by the Binding of Naphthyridine Dimer : Inhibition of the Elongation of a"J.Am.Chem.Soc.. 125. 662-666 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中谷和彦ほか: "Affinity Labeling of a Single Guanine Bulge"J.Am.Chem.Soc.. 125. 8972-8973 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中谷和彦ほか: "Formation and Destruction of the Guanine Quartet in solution Observed by Cold-Spray lonization Mass Spectrometry"J.Am.Chem.Soc.. 126. 557-562 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中谷和彦ほか: "Detection of Guanine-Adenine Mismatches by Surface Plasmon Resonance Sensor carrving Naphthyridine-Asaguinolone Hybrid on the Surface"Nucleic Acids Res.. 32. 278-286 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中谷和彦ほか: "Highly Sensitive Detection of GG Mismatched DNA by Surfaces Immobilized Naphthyridine Dimer through Poly(ethylene oxide) Linkers"Bioorg.Med.Chem.Lett.. 14. 1105-1108 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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