2002 Fiscal Year Final Research Report Summary
Design of the new recognition molecules for the formation of triplex helix DNA at any predetermined sites.
Project/Area Number |
13672218
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Chemical pharmacy
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Research Institution | Kyushu University |
Principal Investigator |
SASAKI Shigeki Faculty of Pharmaceutical Sciences, Prof., 大学院・薬学研究院, 教授 (10170672)
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Project Period (FY) |
2001 – 2002
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Keywords | triplex DNA / artificial nucleobase analog / antigene / recognition of duplex sequence / inhibition of gene expression / recognition molecule / expansion of triplex code / genome-targeting chemistry |
Research Abstract |
Since triplex formation within the major groove of duplex DNA has been proposed as a selective method for specific inhibition of gene expression at a predetermined sequence, a major concern has been to overcome its intrinsic limitation that triplexes are formed only toward homopurine-homopyrimidine sequences of the duplex. That is, pyrimidine bases within the homopurine strand of the duplex inhibit triplex formation; therefore, efforts have been focused on development of a non-natural base structure to stabilize triplexes at such interrupting sites. Nevertheless, triplex formation at any DNA sequence has remained a challenging theme. In this approach, we focused on an antiparallel triplex formed with purine-rich triplex-forming oligonucleotides (TFO), because the antiparallel triplexes are formed under physiological conditions with higher stability than the parallel ones with pyrimidine TFOs. We designed a new general structure of nucleoside analogs bearing an aromatic part for stacking, a base for Hoogesteen hydrogen bonds, and a [3.3.0]bicycooctane structure to fix fix the two former components. The newly designed molecule was named the W-shaped nucleic acid (WNA) after its shape. In the antiparallel orientation, the purine base is expected to form two Hoogesteen hydrogen bonds toward the target purine base within a pyrimidine strand of the duplex, and an aromatic may play a role to maintain stacking interaction of the TFO continuously through the new nucleoside analog. In conclusion, we have revealed that the new W-shaped nucleic acid derivative WNA-bT exhibits high stabilization effect toward a TA interrupting site with high selectivity. In addition, WNA-bC showed selective stabilization toward the duplex having a CG interrupting site. Thus, the new WNA analogs would become new candidates for the formation of non-natural type triplexes with high selectivity and affinity to a TA and to a CG interrupting site.
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Research Products
(14 results)
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[Publications] Sasaki, Shigeki, Yamauchi, Hiroyuki, Nagatsugi, Fumi, Takahashi, Ryo, Taniguchi, Yosuke, Minoru Maeda: "W-Shape Nucleic Acid (WNA) for Selective Formation of Non-Natural Anti-Parallel Triplex Including a TA Interrupting Site"Tetrahedron Letters. 42(39). 6915-6918 (2001)
Description
「研究成果報告書概要(和文)」より
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