Design of Nucleoside Analogs for the Formation of Triplex DNA

Recently, important roles of non-canonical higher order structures of DNA and RNA have been identified in regulation of gene expression. Therefore, the molecules that can target specific DNA and RNA sequences will be useful not only as innovative bio-tools but also as potential candidates for new therapeutic agents. Triplex helix DNA formation with the use of synthetic oligonucleotides (triplex-forming oligonucleotides; TFO) provides a unique method for recognition of duplex DNA leading to inhibition of transcription with high sequence specificity in the antigene method. However, as the stable triplex DNA is formed only with the duplex with homopurine—homopyrimidine sequence, development of TFO as the biological tool has been hampered. This limitation arises from the fact that pyrimidine bases provide one hydrogen bonding site to natural bases within the major groove, and pyrimidine-purine base pairs interrupt triplex formation. Much effort has been devoted to overcome to this problem, and some successful approaches were recently reported with the use of newly designed nucleoside analogs. The author's group also succeeded the development of original nucleoside analogs for the recognition of pyrimidine-purine interrupting sites. This mini-review focuses on the development of nucleoside analogs for the formation of stable triplex DNA.