PHOSPHORYLATED ISONUCLEOSIDES: NEW ANTI-HIV AGENTS

人类免疫缺陷病毒（HIV）的pol基因编码 三种病毒酶，逆转录酶，蛋白酶和整合酶， 对艾滋病毒的复制至关重要。这个项目的重点是发现 这些病毒酶之一的抑制剂，艾滋病毒逆转录酶（HIV RT）。广泛的目标是促进化学和生物化学 具有有用治疗作用的概念上新的核苷和核苷酸 潜在的艾滋病病毒的传染性。这些新化合物， 立体化学定义的替代碳水化合物组分， 与天然核苷和核苷酸的区域异构体，被称为 异核苷和异核苷。一个令人信服的理由 一项调查来自于在这个项目中发现了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IsoddAj。IsoddA 5 '-三磷酸是一种 HIV RT的强效抑制剂（K 16 nM）。这一更新建议旨在扩大 当前项目的成功工作，包括环磷酸盐（MP） 前药（环Sal MP）和水解稳定的膦酰基衍生物， 以便将MP或其等排体直接递送到细胞内。在 此外，新类别的ISO9001具有多个支持理由， 抗HIV活性。合成工作将涉及开发 新的手性异二脱氧核苷及其纯化方法 并通过磁共振、质谱和X射线进行完整表征 方法.目标化合物和前体药物的协同抗病毒研究 将针对HIV-1和HIV-2以及重要的耐药病毒进行形式的研究。 艾滋病毒变异体。抑制HIV致细胞病变效应的数据， 对HIV RT、前病毒DNA合成的抑制、对宿主细胞毒性的影响 包括抑制细胞DNA聚合酶α和γ，以及对治疗 指标将被确定和分析。细胞联合药物研究， 特别是具有协同抑制HIV潜力的那些 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.