ゲノムテクノロジー基盤素材としての架橋型人工核酸BNA  [in Japanese] Bridged Nucleic Acids (BNAs) as a Basic Material for Genome Technology  [in Japanese]

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Abstract

ヒトゲノムプロジェクトの終結が2003年4月に宣言され,今やわれわれは名実ともにポストゲノム時代のまっただ中にあると言える.約30億塩基対もの長さのヒトゲノム配列が解読されたことにより,医療や産業には大きな変革がもたらされようとしており,社会的にも,一塩基多型(SNP)に基づくテーラーメード医療やゲノム情報に基づく分子標的医薬,そして遺伝子を直接標的とした新しい遺伝子医薬などの実現に高い期待が寄せられている.筆者らは,こうしたポストゲノム時代における様々な先端医療や産業の基盤を担う新しいテクノロジーを確立すべく,化学修飾を施した人工的な核酸分子の開発研究に取り組んでいる.筆者らが注目するポストゲノム基盤テクノロジーの1つにアンチジーン法がある(Fig. 1).生体内においてDNAに蓄積された遺伝情報は,mRNAへ転写され,そしてタンパク質へ翻訳される.この一連の流れの中で,DNAからRNAへの転写の過程をオリゴヌクレオチドにより制御しようという手法がアンチジーン法である.

  The completion of the human genome sequencing project will greatly accelerate the development of novel and practical technologies for genome-analysis, diagnostics or therapeutics. Oligonucleotides are playing an important role in these genome technologies, because of their sequence-specific hybridization ability toward the complementary strand. Besides the sequence-specific duplex formation, oligonucleotides are able to form stable triplex structures, which is fundamental to the antigene strategy to regulate gene expression in a living cell. However, two major drawbacks are known in the triplex formation by a natural oligonucleotide: low stability of the triplex and limitations of the target DNA sequence. One promising strategy to overcome these problems is chemical modification of the oligonucleotides. We have developed various bridged nucleic acids (BNAs), and found that the oligonucleotides containing 2′-<i>O</i>,4′-<i>C</i>-methylene bridged nucleic acid (2′,4′-BNA) modification form a stable parallel motif triplex with the double-stranded DNA target under physiological conditions. Some nucleobase analogues to extend the target DNA sequence were designed, synthesized and incorporated into the 2′,4′-BNA structure. The obtained 2′,4′-BNA derivatives containing modified nucleobases effectively recognized a pyrimidine-purine interruption. Some other examples of nucleic acid analogues to overcome the two major drawbacks in the triplex-forming oligonucleotides are also summarized.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 124(11), 781-790, 2004-11-01

    The Pharmaceutical Society of Japan

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Codes

  • NII Article ID (NAID)
    110003666134
  • NII NACSIS-CAT ID (NCID)
    AN00284903
  • Text Lang
    JPN
  • Article Type
    REV
  • ISSN
    00316903
  • NDL Article ID
    7137934
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z19-411
  • Data Source
    CJP  NDL  NII-ELS  J-STAGE 
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