OLIGODEOXYNUCLEOSIDE BORANOPHOSPHATES--NEW DNA ANALOG

寡脱氧核苷磷酸硼盐——新的 DNA 类似物

• 批准号: 6180727
• 负责人: BARBARA RAMSAY SHAW
• 金额: $ 12.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6180727
• 关键词: boron; chemical stability; deoxyribonucleosides; hydropathy; nucleic acid chemical synthesis; nucleic acid structure; nucleoside analog; phosphates; synthetic nucleic acid

DESCRIPTION: A new class of modified nucleic acids, the oligodeoxynucleoside boranophosphates (BH3-ODN), are isoelectronic and iso-ionic analogs of the phosphorothioates and the naturally occurring O-phosphate esters. Studies demonstrate that HB3-ODN possess unique properties and have potential for application as diagnostic and therapeutic agents. Relative to normal DNA, BH3--ODN have increased lipophilicity and are notably resistant to degradation by nucleases. Preliminary data suggest that BH3--ODN support RNAse H induced cleavage of RNA. BH3--ODN can by synthesized enzymatically to give gene-length fragments that are accurate, complementary copies of the parent DNA. A promising new chemical method for synthesizing BH3--ODN is currently being explored. Further applications are planned for solution phase chemistries to solid phase synthesis, making possible for the first time the synthesis of lon oligos with defined sequence, at up to millimolar scale. Other goals of the proposed work are to examine further the unique chemical and biological properties of the boranophosphate oligomers, and develop a novel set of boronated compounds for practical use. The specific aims are to: 1)Develop effective chemical and enzymatic approaches to expedite synthesis of the BH3--ODN of any given length and sequence, in conjunction with appropriate analytical methods to verify the BH3--ODN integrity, base composition, sequence, and length. 2)Investigate and delineate the chemical, biochemical, and biophysical properties of BH3--ODN which are most essential for biochemica and therapeutical applications, including their stability under physiological conditions, nuclease resistance, lipophilicity and ability to cross cell membranes, metabolism, and their ability to form duplexes and triplexes with the complementary DNA and RNA. 3)Examine the potential of BH3--ODN for activating RNAse H in vitro and for arresting translation and transcription. 4 Conjugate BH3--ODN with appropriate functional groups (peptides, phospholipids fluoresce labels, etc.) to facilitate their cell penetration and targeting to specific cell types, and to examine their cell localization. 5) Study the feasibility of employing BH3--ODN to target human viral and genetic diseases. Results will be compared with other modified ODN. Thus, boranophosphates represent and exciting new chemistry on which to build new diagnostic and therapeutic technologies.

描述：一类新的修饰核酸， 寡脱氧核苷硼磷酸（BH 3-ODN）是等电子的， 硫代磷酸酯的等离子类似物和天然存在的 O-磷酸酯。 研究表明HB 3-ODN具有独特的 性质，并具有作为诊断和 治疗剂。 相对于正常DNA，BH 3--ODN增加 亲脂性并且显著地抵抗核酸酶的降解。 初步数据表明，BH 3-ODN支持RNA酶H诱导的切割， 核糖核酸 BH 3-ODN可以通过酶促合成得到基因长度 这些片段是亲本DNA的精确互补拷贝。 一 一种很有前途的合成BH_3的新化学方法--ODN目前正在研究中 探讨了 计划进一步应用于溶液相化学 固相合成，首次使合成成为可能， 有明确序列的离子寡聚体，达到了毫摩尔级。 其他 拟议工作的目标是进一步研究独特的化学品， 的硼磷酸低聚物的生物学特性，并开发一个 用于实际应用的一组新的硼化化合物。 具体目标是 1）开发有效的化学和酶促方法， 任何给定长度和序列的BH 3-ODN的合成， 用适当的分析方法验证BH 3--ODN的完整性， 组成、顺序和长度。 2)调查和描述 BH 3-ODN的化学、生物化学和生物物理性质， 对于生物化学和治疗应用最重要，包括 它们在生理条件下的稳定性，核酸酶抗性， 亲脂性和穿过细胞膜的能力，代谢，及其 与互补DNA和RNA形成双链体和三链体的能力。 3)检测BH 3--ODN体外激活RNA酶H的潜力， 来阻止翻译和转录 4缀合物BH 3--ODN与 合适的官能团（肽，磷脂荧光标记， 等等）。以促进它们的细胞穿透和靶向特定细胞 类型，并检查其细胞定位。 5)研究可否 利用BH 3-ODN靶向人类病毒和遗传疾病。 结果 将与其他改进的ODN进行比较。 因此，硼磷酸盐 代表和令人兴奋的新化学，在此基础上建立新的诊断和 治疗技术