PHOSPHORYLATED ISONUCLEOSIDES: NEW ANTI-HIV AGENTS

人类免疫缺陷病毒(HIV)的pol1基因编码 三种病毒酶，逆转录酶，蛋白酶和整合酶，这三种酶是 对艾滋病毒的复制至关重要。这个项目的重点是发现 其中一种病毒酶，HIV逆转录酶(HIV)的抑制剂 RT)。广泛的目标是对化学和生物化学做出贡献。 概念上的新核苷和核苷酸具有有用的治疗作用 有潜力对抗艾滋病毒的传染性。这些新的化合物，与 立体化学定义的替代碳水化合物成分，即 与天然核苷和核苷酸的区域异构体，称为 同核苷和同核苷酸。这是一个令人信服的理由 调查来自于这个项目中发现的一种有效的抗艾滋病毒药物 活性化合物，(S，S)-异二脱氧腺苷异构体。5‘-三磷酸异构体是一种 强大的HIV RT抑制剂(K16 NM)。这项续签提案旨在扩大 目前项目的成功工作包括环一磷酸(MP) 前体药物(环丙沙星MPS)和水解性稳定的膦酰衍生物 以便将MPS或它们的同位素体直接输送到细胞内。在……里面 此外，具有多重支持原理的新类别的异核苷 抗HIV活性被提出。综合工作将涉及到开发 新型手性异二脱氧核苷及其纯化方法的研究进展 并通过核磁共振、质谱学和X射线进行了完整的表征 方法：研究方法。目标化合物和前药的协作性抗病毒研究 将开展针对艾滋病病毒L和艾滋病病毒2型的表彰，并对其进行重要耐药 艾滋病毒变种人。抑制艾滋病毒的细胞病变作用的数据，关于抑制 HIV RT对前病毒DNA合成的抑制作用，对宿主细胞的细胞毒性 包括抑制细胞DNA聚合酶a和y，以及治疗 指标将被确定和分析。细胞联合药物研究， 特别是那些有可能协同抑制艾滋病毒的药物 传染性，也是有计划的。

The pol gene of the human immunodeficiency virus (HIV) encodes three viral enzymes, reverse transcriptase, protease and integrase, which are critical for the replication of HIV. This project is focused on the discovery of inhibitors of one of these viral enzymes, HIV reverse transcriptase (HIV RT). The broad objectives are to contribute to the chemistry and biochemistry of conceptually new nucleosides and nucleotides with useful therapeutic potential against the infectivity of HIV. These novel compounds, with stereochemically defined surrogate carbohydrate components, that are regioisomeric with the natural nucleosides and nucleotides, are referred to as isonucleosides and isonucleotides. A compelling rationale for this investigation comes from the discovery in this project of a potently anti-HIV active compound, (S,S)-isodideoxyadenosine IsoddAj. IsoddA 5'-triphosphate is a powerful inhibitor of HIV RT (K 16 nM). This renewal proposal seeks to expand the successful work of the current project to include cyclic monophosphate (MP) pro-drugs (cyclo Sal MPs) and hydrolytically stable phosphonyl derivatives in order to deliver the MPs or their isosteres directly inside the cell. In addition, new classes of isonucleosides with multiple supporting rationale for anti-HIV activity are proposed. The synthetic work will involve the development of approaches to the novel, chiral isodideoxynucleosides and their purification and complete characterization by magnetic resonance, mass spectral, and X-ray methods. Collaborative antiviral studies on the target compounds and pro-drug forms will be carried out against HIV-l and HIV-2, and important drug-resistant HIV mutants. Data on inhibition of the cytopathic effect of HIV, on inhibition of HIV RT, on inhibition of proviral DNA synthesis, on host cell cytotoxicity including inhibition of cellular DNA polymerases a, and y, and 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.