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 概念上具有有用治疗潜力的新核苷和核苷酸 对抗艾滋病毒的传染性。这些新化合物，与立体化学 定义的替代碳水化合物成分，与 天然核苷和核苷酸，称为异核苷和 等核苷酸。这次调查的一个令人信服的理由来自于 在这个项目中发现了一种有效的抗艾滋病毒活性化合物， (S，S)-异二脱氧腺苷[(S，S)-异氧A}。5‘-三磷酸是一种强大的 HIV逆转录酶抑制物(Ki16 NM)。这项续签提案旨在扩大 当前项目的成功工作，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，具有多个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 将针对艾滋病毒-1和艾滋病毒-2开展表格，包括抗药性艾滋病毒 分离株。关于抑制艾滋病毒的细胞病变效应的数据，关于抑制 HIV RT，对前病毒DNA合成的抑制，对 HIV-1p-24 Gag蛋白在宿主细胞中的表达 对细胞DNA聚合酶α-β和γ的抑制作用 治疗指标将进行测定和分析。细胞联合用药 研究，特别是那些具有协同抑制作用的研究 艾滋病毒的传染性，也在计划之中。

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 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 [(S,S)-isoddA}. IsoddA 5'-triphosphate is a powerful inhibitor of HIV RT (KI 16 nM). This renewal proposal seeks to expand 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 rationaleS 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-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 proviral DNA synthesis, on inhibition of the expression of HIV-1 p-24 Gag protein, on host cell cytotoxicicty including inhibition of cellular DNA polymerases alphaepsilon beta and gamma, 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.