MOLECULAR APPROACHES TO ANTI-AIDS DRUG DEVELOPMENT

这项拟议中的项目是一项旨在 开发新的化疗药物和方法。主 本研究的目的是提供新的应对策略。 提高抗HIV药物的治疗效果。 提出了合理设计的前药途径，以实现有效 药物渗透到中枢神经系统，延长持续时间 作用并降低细胞间抗病毒活性的变异性。在……里面 以增加选择性，从而减少细胞和 系统性毒性，利用艾滋病毒的不保真性 逆转录酶作为一种新的方法被提出。该项目 专注于1)水溶性化合物的设计、合成和研究 核苷和核苷的亲脂性、膜透性前药衍生物 核苷酸类似物，基于初始阶段的结果 项目；以及2个新的核苷和核苷酸类似物能够 逆转录酶可能错误地整合到DNA中 艾滋病毒复制的抑制剂具有更高的选择性。 该项目的具体目标包括：设计、综合和 嘌呤类和亲脂性水溶性前药形态的表征 嘧啶2‘，3’-二脱氧核苷及其核苷酸衍生物 潜在的抗HIV药物；新型药物的设计、合成和研究 能够被HIV错误结合到病毒DNA中的核苷类似物 逆转录酶；具有代表性的细胞代谢研究 类似物.5‘-的底物和抑制活性的测定 HIV逆转催化反应中的三磷酸衍生物 具有链终止潜力的转录酶，与 细胞DNA聚合酶.不匹配误差产生的研究 体外保真度分析.核苷类似物和核苷类似物的构象分析 用X射线结晶学、分子学研究它们的潜在碱基对 建模和计算机图形技术.抗艾滋病毒的评价 适当测试系统中的活性和细胞毒性；相关性 分子结构、物理化学性质和化学成分 与生物活性的反应。由此产生的结构- 活动关系将构成塑造未来研究的基础 方向。 关于拟议研究项目的意义，它是 很可能除了它们的治疗潜力外，靶子 化合物可以作为研究生化过程的有用工具。 在逆转录病毒感染的细胞中和在HIV感染的细胞中 很特别。

The proposed project is part of a long range research effort aimed at the development of new chemotherapeutic agents and approaches. The main objective of this research is to provide new strategies for the improvement of the therapeutic effectiveness of anti-HIV agents. Rationally designed prodrug approaches are proposed to achieve effective drug penetration into the central nervous system, prolonged duration of action and decreased cell-to-cell variability of antiviral activity. In order to increase selectivity resulting in decreased cellular and systemic toxicity, the exploitation of the lack of fidelity of HIV reverse transcriptase, as a novel approach, is proposed. The project focuses on the design, synthesis and study of 1) water soluble lipophilic, membrane permeable prodrug derivatives of nucleoside and nucleotide analogs, based on the results of the initial phase of the project; and 2 novel nucleoside and nucleotide analogs capable of misincorporation into DNA by reverse transcriptase as potential inhibitors of HIV replication with enhanced selectivity. The specific aims of the project include: design, synthesis and characterization of water soluble lipophilic prodrug forms of purine and pyrimidine 2', 3'-dideoxynucleoside and nucleotide derivatives as potential anti-HIV agents; design, synthesis and study of novel nucleoside analogs capable of misincorporation into viral DNA by HIV reverse transcriptase; study of the cellular metabolism of representative analogs; determination of substrate and inhibitory activity of the 5'- triphosphate derivatives in the reaction catalyzed by HIV reverse transcriptase with chain-terminating potential, in comparison with the cellular DNA polymerases; study of mismatch error production using in vitro fidelity assays; conformational analysis of nucleoside analogs and their potential base-pairs using X-ray crystallography, molecular modeling and computer graphics techniques; evaluation of anti-HIV activity and cytotoxicity in appropriate test systems; the correlation of molecular structures, physicochemical properties and chemical reactivities with biological activities. The resulting structure- activity relationships will form the basis for shaping future research directions. With respect to the significance of the proposed research project, it is likely that in addition to their therapeutic potential, the target compounds may serve as useful tools in the study of biochemical processes in retrovirus infected cells in general and in HIV infected cells in particular.