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Design of functional molecules for selective recognition and reaction to the duplex DNA

用于选择性识别和反应双链 DNA 的功能分子设计

基本信息

批准号：
15390007
负责人：
SASAKI Shigeki
金额：
$ 9.41万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390007/
关键词：
Genome-targeting molecular recognition reactive molecule duplex DNA nitrosyl transfer triplex DNA minor-groove binder artificial nucleoside analog マイナーグループ結合

项目摘要

Molecules that can target DNA or RNA with high efficiency and specificity are of great interest because of potential applications to modulation of gene expression at a specific site. Our approach in genome-targeting chemistry has been focused on development of reactive molecules with high base- as well as sequence selectivity. In this study, three contents. In this study, three methods have been investigated, which include (1) DNA/RNA hybridization, (2) triplex DNA formation, (3) DNA minor-groove binding.In the approach with DNA/RNA hybridization, we investigated the new reactive molecules that can discriminate a single nucleoside difference. We have already developed new cross-linking agents with high selectivity. In this study, the same design concept has been applied to develop a reactive molecule for nitrosyl group transfer. As a result, it has been revealed that S-nitroso thioguanosine can transfer its nitroso group to the amino group of cytosine and 5-methylcytosine selectively, … More and that the nitroso-transferred amino group suffers easy deamination to give uracil or thymine.In the project for new nucleoside analogs for the formation of stable triplexes having interrupting base pairs, we have continued searching new nucleoside analogs having the WNA (W-shaped nucleoside analog) skeleton. The WNA analogs contain a benzene ring and a heterocyle as a recognition part on the bicyclo[3.3.0]octane skeleton. In this study, a variety of heterocyclic parts have been introduced to the bicyclo[3.3.0]octane skeleton and their triplex-forming ability has been tested. As a result, in addition to the previous WNA analog (WNA-βT) that is selective to a TA interrupting site, the new analog WNA-βC has been identified as a selective base for a CG interrupting site.In this study, new DNA-binding ligands were designed to mimic Chromomycin A3 (CRA3) which contains a hydroxylated tetrahydroanthracene chromophore substituted with di- and tri-saccharides. The trisaccharide part of CRA3 that is supposed to contribute to form the Mg^<2+>-coordinated dimer was expected to be mimicked by a simple alkyl group attached to the chromophore part as new model compounds. The present study has successfully demonstrated that the new ligands form Mg^<2+>-coordinated dimer complexes to exhibit DNA-binding affinity. Less

能够以高效率和特异性靶向DNA或RNA的分子由于在特定位点调节基因表达的潜在应用而受到极大关注。我们在基因组靶向化学方面的方法一直专注于开发具有高碱基和序列选择性的反应性分子。在本研究中，有三个内容。本研究主要研究了三种方法，即（1）DNA/RNA杂交法、（2）三链DNA形成法、（3）DNA小沟结合法，在DNA/RNA杂交法中，我们研究了能够区分单个核苷差异的新型反应分子。我们已经开发出具有高选择性的新型交联剂。在本研究中，相同的设计概念已被应用于开发用于亚硝酰基转移的反应分子。结果表明，S-亚硝基硫代鸟苷可以选择性地将其亚硝基转移到胞嘧啶和5-甲基胞嘧啶的氨基上， ...更多信息亚硝基转移的氨基容易脱氨基而得到尿嘧啶或胸腺嘧啶。在用于形成具有中断碱基对的稳定三链体的新核苷类似物的项目中，我们继续寻找具有WNA（W形核苷类似物）骨架的新核苷类似物。WNA类似物含有一个苯环和一个杂环作为双环[3.3.0]辛烷骨架上的识别部分。在本研究中，各种杂环部分已被引入到双环[3.3.0]辛烷骨架和他们的三链体形成能力进行了测试。因此，除了之前对TA中断位点具有选择性的WNA类似物（WNA-βT）之外，新的类似物WNA-βC已被确定为CG中断位点的选择性碱基。在这项研究中，设计了新的DNA结合配体来模拟色霉素A3（CRA 3），其中含有被双糖和三糖取代的羟基化四氢蒽发色团。CRA 3的三糖部分被认为有助于形成Mg^<2+>-配位的二聚体，预计将被连接到发色团部分的简单烷基模拟为新的模型化合物。本研究成功证明了新配体形成Mg^<2+>配位二聚体复合物，表现出DNA结合亲和力。少

项目成果

期刊论文数量（66）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nagatsugi F, Sasaki S., Miller P.S., Seidman M.M.: "Site-Specific Mutagenesis by Triple-Helix Forming Oligonucleotides Containing a Reactive Nucleoside Analogue."Nucleic Acids Res.. 31・6. e31 (2003)

Nagatsugi F、Sasaki S.、Miller P.S.、Seidman M.M.：“含有反应性核苷类似物的三螺旋形成寡核苷酸的位点特异性诱变。”31・6。

DOI：
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通讯作者：

Shigeki Sasaki, Yosuke Taniguchi, Ryo Takahashi, Yusuke Senko, Keiichi Kodama, Fumi Nagatsugi, Minoru Maeda: "Selective Formation of Stable Triplexes Including a TA or a CG Interrupting Site with New Bicyclic Nucleoside Analogs (WNA)"J.Amer.Chem.Soc.,516-

Shigeki Sasaki、Yosuke Taniguchi、Ryo Takahashi、Yusuke Senko、Keiichi Kodama、Fumi Nagatsugi、Minoru Maeda：“用新的双环核苷类似物 (WNA) 选择性形成包括 TA 或 CG 中断位点的稳定三链体”J.Amer.Chem。