PHOSPHORYLATED ISONUCLEOSIDES--NEW ANTIHIV AGENTS

磷酸异核苷--新型抗艾滋病药物

• 批准号: 2672128
• 负责人: VASU NAIR
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672128
• 关键词: 2'3' dideoxynucleoside; AIDS; DNA directed DNA polymerase; RNA directed DNA polymerase; X ray crystallography; antiAIDS agent; circular dichroism; drug design /synthesis /production; enzyme activity; human immunodeficiency virus 1; human immunodeficiency virus 2; integrase; mass spectrometry; nuclear magnetic resonance spectroscopy; pharmacokinetics; prodrugs; stereochemistry; ultraviolet spectrometry

The long term goals of this project are to contribute to the chemistry and biochemistry of conceptually novel nucleosides, nucleotides and related analogs and derivatives with useful therapeutic potential against the infectivity of the human immunodeficiency virus (HIV). The specific aims of this project are the design, synthesis, enzymology and anti-HIV studies of a new family of structurally and stereochemically defined compounds that are isomeric with the natural nucleosides and nucleotides and that are referred to as isonucleosides and isonucleotides. A potently anti-HIV active isodideoxynucleoside [4(S)-(6-amino-9H-purin-9-yl)tetra- hydro-2(S)-furanmethanol, (S,S)-IsoddA] has been discovered in the current grant project. IsoddA as its 5'-triphosphate is also a very strong inhibitor of the viral enzyme, HIV reverse transcriptase. This renewal proposal seeks: (1) to continue the successful work of the current project on conceptually new isonucleosides and their phosphorylated derivatives as potential anti-HIV agents and inhibitors of HIV reverse transcriptase; (2) to investigate a new series of strategically modified isonucleotides as potential inhibitors of another key viral enzyme, HIV integrase. The synthetic work proposed will involve the development of approaches to optically active novel isodideoxynucleosides and isodideoxynucleotides and their purification and complete characterization by NMR, FAB and electrospray mass spectrometry, and X-ray crystallography. Collaborative antiviral studies on the target compounds and pro-drug forms will be carried out against HIV-1 and HIV-2, including drug-resistant HIV isolates. Data on inhibition of the cytopathic effect of HIV, on inhibition of HIV RT, on inhibition of HIV integrase-catalyzed reactions, on inhibition of integrase-DNA binding, on inhibition of proviral DNA synthesis, on host cell cytotoxicity including inhibition of cellular DNA polymerases alpha, beta and gamma on therapeutic indexes will be determined and analyzed. Cellular combination drug studies, particularly those having the potential for synergistic inhibition of HIV infectivity, are also planned.

该项目的长期目标是为化学做出贡献 以及概念上新型核苷，核苷酸和生物化学 具有有用的治疗潜力的相关类似物和衍生物 人类免疫缺陷病毒（HIV）的感染性。 具体 该项目的目的是设计，合成，酶学和抗HIV 研究一个新的结构和立体定义的家族 具有天然核苷和核苷酸的异构体的化合物 并且称为异核苷和异核苷酸。一个有力的 抗HIV活性异二核苷[4（s） - （6-Amino-9h-Purin-9-基）TETRA- 氢-2（S）-Furanmethanol，（S，S）-Isodda]在 当前的赠款项目。 ISODDA，因为它的5'-三磷酸也是一个非常 病毒酶，HIV逆转录酶的强抑制剂。这 更新提案寻求：（1）继续成功的工作 从概念上进行新的Isonucleosides及其目前的项目 磷酸化衍生物作为潜在的抗HIV药物和抑制剂 HIV逆转录酶； （2）调查一系列新的 策略性修改的异核苷酸作为另一个潜在的抑制剂 关键病毒酶，HIV整合酶。提议的合成工作将涉及 光学活跃小说的方法的发展 异氧化核苷和异氧化核苷酸及其纯化 并通过NMR，Fab和Electrospray质量进行完整的表征 光谱法和X射线晶体学。 协作抗病毒研究 在目标化合物和亲毒品表格上将进行反对 HIV-1和HIV-2，包括耐药的HIV分离株。 数据上 抑制HIV的细胞质效应，对HIV RT的抑制，对 抑制HIV积分酶催化反应，以抑制 积分酶-DNA结合，抑制前病毒DNA合成，对宿主 细胞毒性包括抑制细胞DNA聚合酶α， 将确定和分析有关治疗指数的β和伽玛。 细胞组合药物研究，尤其是那些 协同抑制HIV感染性的潜力也是 计划。