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

Abstract

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'-O,4'-C-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.