Attempts to the formation of stable unnatural triplex DNA using W-shaped Nucleoside Analogs and their application to the inhibition of the gene expression

Abstract

In an antiparallel triplex DNA, the purine-rich TFOs bind to the duplex DNA in homopurine/homopyrimidine regions by two reverse Hoogsteen hydrogen bonds, and it is possible to inhibit the gene expressions as an antigene strategy. Triplex DNA has intrinsic limitations in the sequences that can be targeted by TFOs. The pyrimidine bases in purine-rich target region hamper the stable triplex DNA, because these bases have one hydrogen bonding site in the TFO binding site. Therefore we designed the original bicyclic nucleoside analogs (WNA) to recognize the TA or CG base pairs and to develop the gene targeting drugs. It was achieved that WNA analogs recognized the TA or CG base pair with high selectivity. Moreover, subsequent studies showed that the combination use of WNA analogs, an aromatic or a recognition base modified WNAs, could expand the triplex recognition codes. We are applying TFOs having WNA analogs to the cancer cells to study the inhibition of the gene expression.