PHOSPHORYLATED ISONUCLEOSIDES: NEW ANTI-HIV AGENTS

磷酸化异核苷：新型抗艾滋病毒药物

• 批准号: 6313281
• 负责人: VASU NAIR
• 金额: $ 20.21万
• 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 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6313281
• 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，它们是 对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 RT）。广泛的目标是为化学和生物化学做出贡献 从概念上使用有用治疗的新型核苷酸和核苷酸 抗艾滋病毒感染力的潜力。这些新颖的化合物，带有 立体定义的替代碳水化合物成分，即 具有天然核苷和核苷酸的区域异构体称为 异核苷和异核苷酸。一个引人入胜的理由 调查来自该项目中有效的抗HIV的发现 活性化合物，（s，s） - 异地氧化核苷等异源。 ISODDA 5'-三磷酸盐是 HIV RT的强大抑制剂（K 16 nm）。该更新提案旨在扩大 当前项目的成功工作，包括循环单磷酸盐（MP） 促毒物（Cyclo sal MP）和水解稳定的磷衍生物 为了将MPS或它们的等值器直接输送到电池内。在 此外，新类的异核苷类，具有多个支持理由 提出了抗HIV活性。合成工作将涉及开发 小说，手性异地核苷及其纯化的方法 并通过磁共振，质谱和X射线进行完整的表征 方法。关于目标化合物和亲药的协作抗病毒研究 形式将针对HIV-L和HIV-2进行，并具有重要的药物耐药性 艾滋病毒突变体。关于抑制艾滋病毒细胞病毒作用的数据，对抑制作用 HIV RT的抑制前病毒DNA合成，对宿主细胞毒性 包括抑制细胞DNA聚合酶A和Y，以及治疗性 将确定和分析索引。细胞组合药物研究， 特别是那些具有协同抑制艾滋病毒的潜力的人 还计划了感染力。