PHOSPHORYLATED ISONUCLEOSIDES: NEW ANTI-HIV AGENTS

磷酸化异核苷：新型抗艾滋病毒药物

• 批准号: 6510705
• 负责人: VASU NAIR
• 金额: $ 2.12万
• 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 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6510705
• 关键词: 2'3' dideoxynucleoside; DNA directed DNA polymerase; RNA directed DNA polymerase; X ray crystallography; antiAIDS agent; drug design /synthesis /production; electrospray ionization mass spectrometry; enzyme activity; human immunodeficiency virus 1; human immunodeficiency virus 2; integrase; nuclear magnetic resonance spectroscopy; pharmacokinetics; prodrugs; stereochemistry; ultraviolet spectrometry

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.

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 对于艾滋病毒的复制至关重要。该项目的重点是发现 这些病毒酶之一的抑制剂，HIV逆转录酶（HIV 转发）。广泛的目标是为化学和生物化学做出贡献 具有有用治疗作用的概念性新核苷和核苷酸 对抗艾滋病毒传染性的潜力。这些新颖的化合物，具有 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被称为 异核苷和异核苷酸。对此的一个令人信服的理由 调查源于该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 IsoddAj。 IsoddA 5'-三磷酸是 HIV RT 的强效抑制剂 (K 16 nM)。本次更新提案旨在扩大 当前项目的成功工作包括环状单磷酸盐（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，具有多种支持原理的新类异核苷 提出了抗HIV活性。综合工作将涉及开发 新型手性异双脱氧核苷的方法及其纯化 并通过磁共振、质谱和 X 射线进行完整表征 方法。目标化合物和前药的抗病毒合作研究 形式将针对 HIV-1 和 HIV-2 以及重要的耐药性进行 HIV突变体。抑制 HIV 细胞病变效应的数据 HIV RT、抑制前病毒 DNA 合成、对宿主细胞的细胞毒性 包括抑制细胞 DNA 聚合酶 a 和 y，以及治疗作用 确定并分析指标。细胞组合药物研究， 特别是那些具有协同抑制 HIV 潜力的药物 传染性，也在计划之中。