MOLECULAR APPROACHES TO ANTI-AIDS DRUG DEVELOPMENT

拟议的项目是一项长期研究工作的一部分，旨在 开发新的化学治疗剂和方法。 主要 本研究的目的是提供新的战略， 提高抗HIV药物的治疗效果。 提出了合理设计的前药方法，以实现有效的 药物渗透到中枢神经系统，持续时间延长 抗病毒活性的细胞间变异性降低。 在 为了增加选择性，导致细胞和 全身毒性，利用艾滋病毒缺乏保真度 逆转录酶作为一种新的方法被提出。 项目 重点介绍了1）水溶性 核苷的亲脂性、膜可渗透的前药衍生物， 核苷酸类似物，基于初始阶段的结果， 项目;和2种新的核苷和核苷酸类似物， 通过逆转录酶错误掺入DNA， 具有增强的选择性的HIV复制抑制剂。 该项目的具体目标包括：设计、综合和 嘌呤的水溶性亲脂性前药形式的表征 嘧啶2 ′，3 ′-双脱氧核苷和核苷酸衍生物， 潜在的抗HIV药物;新的抗HIV药物的设计、合成和研究 能被HIV错误掺入病毒DNA的核苷类似物 逆转录酶;代表性的 类似物.5 '-氨基丁酸的底物和抑制活性的测定 三磷酸衍生物在HIV逆转催化反应中 具有链终止潜力的转录酶，与 细胞DNA聚合酶;错配错误产生的研究 体外保真度测定;核苷类似物的构象分析， 利用X射线晶体学、分子 建模和计算机图形技术;抗艾滋病毒的评价 适当试验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性质 与生物活性反应。 由此产生的结构- 活动关系将构成未来研究的基础 方向 关于拟议研究项目的重要性， 很可能除了它们的治疗潜力， 化合物可以作为研究生物化学过程的有用工具 在逆转录病毒感染的细胞中， 特别的。

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.