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Boranophosphate DNA: RNA Hybrids as Probes of RNase H

硼磷酸 DNA：作为 RNase H 探针的 RNA 杂交体

基本信息

批准号：
6848312
负责人：
BARBARA RAMSAY SHAW
金额：
$ 30.83万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6848312
关键词：
antisense nucleic acid boron chemical stability endoribonucleases enzyme activity nucleic acid chemical synthesis nucleic acid metabolism nucleic acid probes nucleic acid structure nucleoside analog oligonucleotides pharmacokinetics phosphates ribonuclease H synthetic nucleic acid

项目摘要

DESCRIPTION (provided by applicant): The oligonucleoside boranophosphates (BH3--ODN) are a new class of phosphorus modified oligonucleotides that differ chemically from natural DNA in that a borane (BH-) group replaces one of the non-bridging oxygens in the phosphodiester backbone. BH3--ODN are more lipophilic and much more resistant to nucleases than natural DNA; they form Watson-Crick duplexes, and activate the Rnase H-mediated cleavage of complementary RNA. The boranophosphates join the natural phosphodiester, the (mono-and di-) thioates, and the more-nuclease-susceptible 2'-F-arabinonucleic acids, as the only classes of oligonucleotides that by themselves can orchestrate mRNA degradation in RNA/oligonucleotide hybrids via the enzyme RNase H. Despite recent improvements in the utility of antisense oligonucleotides in vivo, further progress is still needed. The goals of the proposed work are: (1) To synthesize a set of borano phosphate oligonucleotides and mixed-backbone chimeras targeted against the ras gene; (2) To evaluate the potential of BH3--ODN and chimeras to activate Tnase H1; (3) To evaluate biophysical properties of BH3--ODN including the thermodynamics, structure, and kinetics of their hybridization with RNA oligonucleotides and to study the kinetics of hydrolysis of RNA in BH3--ODN /RNA/Rnase H complexes. (4) To examine penetration of BH3-ODN and localization in cells, and other pharmacological properties; and (5) to probe the sequence and structural requirements for Rnase H specificity through our chemistry. The boranophosphates provide a new platform for probing the subtle effects of structure and sequence on RNase H catalysis. Our overall goals are to better understand the unique chemical and biological properties of boranophosphate oligonucleotides and gain further insight into the mechanism of action of RNase H and antisense agents. This information should allow us to design more potent antisense drugs for treating cancer and viral diseases.

描述（由申请人提供）：硼代磷酸盐（BH 3-ODN）是一类新的磷修饰的寡核苷酸，在化学上与天然DNA不同，因为硼烷（BH-）基团取代了其中一个磷酸二酯骨架中的非桥氧。BH 3-ODN更多亲脂性和更耐核酸酶比天然DNA;他们形成沃森-克里克双链体，并激活RNase H介导的切割互补RNA硼磷酸盐加入天然磷酸二酯，（单-和二-）硫代酸酯，和更核酸酶敏感的2 '-F-阿拉伯糖核酸酸，作为寡核苷酸的唯一类别，通过酶协调RNA/寡核苷酸杂合体中的mRNA降解核糖核酸酶H.尽管最近反义核酸的应用有所改进，然而，在体内的寡核苷酸中，仍需要进一步的进展。的目标本文的主要工作是：（1）合成一组硼磷酸寡核苷酸和靶向ras基因的混合骨架嵌合体;（2）评估 BH_3--ODN和嵌合体激活Tnase H_1的潜力;（3）评估 BH 3--ODN的生物物理性质，包括热力学、结构和它们与RNA寡核苷酸杂交的动力学，并研究 BH_3-ODN /RNA/RNase H复合物中RNA水解的动力学。(4)到检查BH 3-ODN的渗透和在细胞中的定位，以及其他药理学性质;和（5）探测序列和结构通过我们的化学对RNase H特异性的要求。的硼磷酸盐提供了一个新的平台，用于探测结构和序列对RNase H催化作用。我们的总体目标是更好地了解硼磷酸盐独特的化学和生物特性寡核苷酸，并进一步了解RNase的作用机制 H和反义试剂。这些信息可以让我们设计出更有效的用于治疗癌症和病毒性疾病的反义药物。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reading, writing, and modulating genetic information with boranophosphate mimics of nucleotides, DNA, and RNA.

使用核苷酸、DNA 和 RNA 的硼磷酸盐模拟物读取、写入和调节遗传信息。

DOI：
10.1196/annals.1281.004
发表时间：
2003
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Shaw,BarbaraRamsay;Dobrikov,Mikhail;Wang,Xin;Wan,Jing;He,Kaizhang;Lin,Jin-Lai;Li,Ping;Rait,Vladimir;Sergueeva,ZinaidaA;Sergueev,Dmitri
通讯作者：
Sergueev,Dmitri

Synthesis of 9-fluorenemethyl boranophosphonodiphosphate via an H-phosphonate approach.

通过 H-膦酸酯方法合成 9-芴甲基硼膦二磷酸酯。