MOLECULAR APPROACHES TO ANTI-AIDS DRUG DEVELOPMENT

抗艾滋病药物开发的分子方法

• 批准号: 3141454
• 负责人: THOMAS I KALMAN
• 金额: $ 12.73万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3141454
• 关键词: X ray crystallography; antiAIDS agent; antiviral agents; computer graphics /printing; conformation; cytotoxicity; drug design /synthesis /production; drug metabolism; human immunodeficiency virus; membrane permeability; neurotoxins; nucleoside analog; nucleotide analog; phosphates; prodrugs; reverse transcriptase inhibitors; tissue /cell culture; virus replication

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 existing anti-AIDS drugs by introducing novel structural modifications based on molecular, biochemical and pharmacologic considerations. The proposed project focuses on the design, synthesis and study of membrane permeable prodrug derivatives of nucleoside and nucleotide analogs as potential inhibitors of human immunodeficiency virus (HIV) replication. The choice and design of target structures take into account the results of preclinical studies and current clinical experience with nucleoside analogs and aim at: effective penetration into the central nervous system; prolonged duration of action; reduced cytotoxicity and systemic toxicity; and increased intracellular availability of phosphorylated derivatives minimizing the cell-to-cell variations of antiviral activity. The specific aims of the proposed research include the design, synthesis and characterization of lipophilic prodrug forms of 2', 3'-dideoxy- nucleoside analogs as potential inhibitors of HIV replication; the study of the factors influencing the hydrolytic conversion of prodrugs to their intracellularly active forms and elucidation of the mechanisms of these reactions; conformational analysis and molecular modelling of target compounds using X-ray crystallography, molecular mechanics calculations and computer graphics techniques; the study of the cellular uptake and metabolism of radioactive isotope labelled derivatives; the measurement of reverse transcriptase inhibitory activity of the 5'-triphosphate derivatives of selected analogs; and the exploration of the usefulness of differentiating neuroblastoma cells in culture as an in vitro model system for neurotoxicity. All target compounds will be made in sufficient quantities for evaluation in various test systems for anti-HIV activity and cytotoxicity. Based on the results obtained, structure-activity relationships will be established to shape future research directions. It is likely that in addition to their potential therapeutic utility, the proposed analogs may serve as useful tools in the study of biochemical processes in retrovirus infected cells.

拟议的项目是一项长期研究工作的一部分，旨在 开发新的化疗药物和方法。 主要 本研究的目的是为改进提供新的策略 评估现有抗爱滋病药物的疗效， 基于分子、生物化学和生物化学的新的结构修饰， 药理学考虑。 本项目的重点是设计， 核苷类前体药物透膜衍生物合成与研究 和核苷酸类似物作为人类免疫缺陷的潜在抑制剂 病毒（HIV）复制。 目标结构的选择和设计 考虑到临床前研究和当前临床研究的结果， 核苷类似物的经验，旨在：有效渗透到 中枢神经系统;延长作用时间;减少 细胞毒性和全身毒性;以及细胞内 磷酸化衍生物的可用性最小化了细胞间的 抗病毒活性的变化。 本研究的具体目标包括设计、合成 和2 ′，3 ′-双脱氧- 核苷类似物作为HIV复制的潜在抑制剂的研究 影响前药水解转化为其 细胞内活性形式和阐明这些机制 反应;目标的构象分析和分子建模 使用X射线晶体学、分子力学计算和 计算机图形技术;细胞摄取的研究， 放射性同位素标记衍生物的代谢; 5 '-三磷酸的逆转录酶抑制活性 选择类似物的衍生物;和有用的探索， 分化培养的神经母细胞瘤细胞作为体外模型系统 神经毒性 所有目标化合物将以足够的量进行评价 在抗HIV活性和细胞毒性的各种测试系统中。 基于 根据所得结果，建立构效关系 来塑造未来的研究方向。 很可能除了 它们的潜在治疗效用，所提出的类似物可用作 逆转录病毒感染的生物化学过程研究中的有用工具 细胞