Development of bridged nucleic acid analogues for antigene technology.
In the last decade, increased efforts have been directed toward the development of oligonucleotide-based technologies for genome analyses, diagnostics, or therapeutics. Among them, an antigene strategy is one promising technology to regulate gene expression in living cells. Stable triplex formation between the triplex-forming oligonucleotide (TFO) and the target double-stranded DNA (dsDNA) is fundamental to the antigene strategy. However, there are two major drawbacks in triplex formation by a natural TFO: low stability of the triplex and limitations of the target DNA sequence. To overcome these problems, we have developed various bridged nucleic acids (BNAs), and found that the 2',4'-BNA modification of oligonucleotides strongly promotes parallel motif triplex formation under physiological conditions. Some nucleobase analogues to extend the target DNA sequence were designed, synthesized, and introduced into the 2',4'-BNA structure. The obtained 2',4'-BNA derivatives with unnatural nucleobases effectively recognized a pyrimidine-purine interruption in the target dsDNA. Some other examples of nucleic acid analogues for stable triplex formation and extension of the target DNA sequence are also summarized.
Obika
Satoshi
S
Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan. obika@phs.osaka-u.ac.jp
D015870:Gene Expression / Q000187:drug effects*; D015316:Genetic Therapy; D008958:Models, Molecular; D009696:Nucleic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*
D009696:Nucleic Acids