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Control of Gene Expression by Functional and Artificial Nucleic Acids

功能性和人工核酸对基因表达的控制

基本信息

批准号：
18550151
负责人：
OBIKA Satoshi
金额：
$ 2.71万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18550151/
关键词：
Nucleic Acids Oligonucleoides Antigene Control of Gene Expression Bridged Nucleic Acids DNA Triplex DNA 三重鎖核酸

项目摘要

In order to develop a novel strategy to control a gene expression, an olignnucleotidc-functional molecule conjugate has been synthesized and its biological properties were also studied. The results are summarized below.1) Some heterocyclic compounds were designed, synthesized and incorporated into a bridged nucleic acid skeleton. The obtained bridged nucleic acids bearing unnatural nucleobases were also introduced into oligonucleotides, and their triplex-forming ability was investigated. Very interestingly, it was found that the recognition of pyrimicline-purine interruption site was successfully achieved by the bridged nucleic acid derivatives /2) As a convenient method to introduce a functional group into oligonucleotides, a post-elongation modification method based on Click chemistry was developed. Furthermore, some oligonucleotides conjugated with a transcription factor-binding site (double stranded DNA) were also successfully prepared.3) The oligonucleotides bearing unnatrural nucleobases prepared above were transfected into living cells, and their ability to control gene expression was evaluated. The oligonucleotides bearing unnatural nucleobases, by themselves or together with the antigene-block strategy developed by our group, showed effective regulation of gene expression. Furthermore, the oligonucleotides conjugated with a transcription factor-binding site promoted the target gene expression. These results are of great interest and would be useful for further biological application.4) A relationship between chemical structures of oligonucleotide analogues and their triplex-forming ability was evaluated in detail, and the novel bridged nucleic acid, of which triplex-forming ability was higher than that of the pinto-type BNA, was successfully developed.

为了开发一种新的调控基因表达的策略，合成了寡核苷酸-功能分子偶联物，并对其生物学性质进行了研究。主要研究结果如下：1）设计、合成了一些杂环化合物，并将其引入到桥联核酸骨架中。将所获得的带有非天然核碱基的桥接核酸也引入寡核苷酸中，并研究它们的三链体形成能力。非常有趣的是，发现通过桥接的核酸衍生物成功地实现了嘧啶霉素-嘌呤中断位点的识别/2）作为将官能团引入寡核苷酸的方便方法，开发了基于点击化学的延伸后修饰方法。3）将上述制备的含有非天然碱基的寡核苷酸转染到活细胞中，观察其调控基因表达的能力。带有非天然核碱基的寡核苷酸，单独或与我们小组开发的抗原阻断策略一起，显示出对基因表达的有效调节。此外，与转录因子结合位点缀合的寡核苷酸促进靶基因的表达。这些结果对进一步的生物学应用具有重要意义。4）详细研究了寡核苷酸类似物的化学结构与其三链体形成能力之间的关系，并成功构建了三链体形成能力高于pinto型BNA的新型桥联核酸。