PHOSPHORYLATED ISONUCLEOSIDES--NEW ANTIHIV AGENTS

该项目的长期目标是促进化学 和生物化学的概念新颖的核苷，核苷酸和 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）的传染性。 具体 本项目的目标是设计、合成、酶学和抗HIV 结构和立体化学定义的新家族的研究 与天然核苷和核苷酸异构的化合物 并且被称为异构体和异构体。A有效地 抗HIV活性异二脱氧核苷[4（S）-（6-氨基-9H-嘌呤-9-基）四- 氢-2（S）-呋喃甲醇，（S，S）-IsoddA]已在 目前的赠款项目。 IsoddA作为其5 '-三磷酸也是一种非常好的 病毒酶HIV逆转录酶的强力抑制剂。这 更新建议的目的是：（1）继续成功的工作， 目前关于概念上新的互联网方面及其 作为潜在抗HIV剂和抑制剂的磷酸化衍生物 HIV逆转录酶;（2）研究一系列新的 作为另一种药物的潜在抑制剂的策略性修饰的异环磷酰胺 关键病毒酶，HIV整合酶。拟议的综合工作将涉及 光学活性新颖化合物制备方法的发展 异双脱氧核苷和异双脱氧核苷酸及其纯化 并通过NMR、FAB和电喷雾质谱进行完整表征 光谱学和X射线晶体学。 合作抗病毒研究 对目标化合物和前药形式的研究将针对 HIV-1和HIV-2，包括耐药HIV分离株。 数据 抑制HIV的细胞病变效应，抑制HIV RT， 抑制HIV整合酶催化的反应， 整合酶-DNA结合，对宿主前病毒DNA合成的抑制 细胞毒性包括抑制细胞DNA聚合酶α， 将测定和分析β和γ对治疗指数的影响。 细胞联合药物研究，特别是那些具有 潜在的协同抑制艾滋病毒感染，也是 计划好了

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.