Design and Synthesis of New Recognition Molecules for the Sequence-Selective Triple Helical DNA Formation

点击翻译按钮获取中文摘要

The triplex formation between the duplex and a single strand DNA has been shown to inhibit transcription at the specific DNA site, and expected as a new biological tool and a new therapeutic method in the so-called antigene strategy. However, native oligonucleotides can form triplexes only within the major groove of the homopurine-homopyrimidine stretch of DNA,and the triplex is destabilized either at a TA or a CG interrupting site. Thus, for expansion of the target DNA sequence, several groups have been attempting to develop non-native nucleobases for binding a TA or a CG base pair, but these problems have not yet been generally solved. We have designed new nucleobase 1 (BIG or B) to form a base triplet with a CG base pair selectively through Hoogsteen-type hydrogen bonds. In this study, we synthesized the oligonucleotide incorporating the non-native base 1 (B), with which we have investigated triplex formation with several duplex DNAs. As a result, it has been demonstrated that the oligonucleotide incorporating 1 forms triplexes by recognizing a CG base pair within a homopurine-homopyrimidine motif. In addition, it has been also revealed that the new non-native base (2) can stabilize a triplex at a CG site more selectively than 1, and that the selective triplex formation at a TA site is enabled by the new non-native base (3). To our knowledge, these new bases are the first ones that form nonnative-type triplexes selectively with comparable stability with native-type triplexes. Therefore, these non-native bases (1,2,3) will become potential candidates to expand the target sequence containing CG and TA interrupting sites.