POTENTIAL SYNERGISTIC INHIBITORS OF HIV INFECTIVITY

这项研究计划的长期目标是为 新一代核苷和杂环体系的发现 有效的治疗潜力对抗艾滋病毒-1、艾滋病毒-2和 具有抗药性的艾滋病毒变种。这项建议的具体目标是 新型化合物的合成和抗HIV研究 艾滋病毒生命周期两个阶段的BE抑制剂，即早期阶段 涉及逆转录(艾滋病毒逆转录酶抑制剂)和后期 涉及转录HIV基因表达(TAT抑制剂)。 被选为抑制HIV RT的前体药物的化合物有 立体化学定义的新型脱氧核苷 碳水化合物部分的过度修饰和设计为TAT的那些 抑制剂是手性杂环体系，属于 氨基苯并二氮类药物家族。有关于有效的抗艾滋病毒的文献 两种抑制剂家族的活性。此外， 选择这些化合物进行研究包括，在适当的情况下， 对磷酸化、细胞稳定性、生物利用度的考虑 和宿主细胞毒性。综合工作将涉及到开发 两个化合物家族的方法，这样他们就可以 以立体化学定义的、光学纯的形式生产的。 包括最终目标分子的立体化学的表征 将通过多核核磁共振波谱、高分辨率FAB 质谱学，紫外线和旋光性数据，元素分析和 单晶X射线数据。稳定性研究，包括行为 对于选定的核苷和核苷酸代谢酶将是 调查过了。高纯度形式的协作性抗病毒研究 在目标化合物中，它们的衍生物和亲药物形式将是 针对艾滋病毒-1、艾滋病毒-2和抗药性艾滋病毒分离株开展了这项工作。一个 将多个细胞株用于毒性、对HIV-1p24的抑制 抑制HIV RT的GAG蛋白对前病毒DNA的抑制作用 合成、对TAT的抑制以及对治疗指标的影响 进行了测定和分析。细胞联合药物治疗研究 特别是涉及协同抑制艾滋病毒与 抗病毒活性的手性氨基苯并二氮类药物(TAT抑制剂)和新的 或已知的活性核苷和核苷酸(HIV RT抑制剂)是 有计划的。建议的化合物很有可能是 抗病毒有用，这项调查将有助于填补一些 在这一领域的知识差距。

The long term goals of this research program are to contribute tot he discovery of new generation nucleosides and heterocyclic systems with useful therapeutic potential against the infectivity of HIV-1, HIV-2 and drug-resistant HIV variants. The specific aims of this proposal are the synthesis and anti-HIV studies of novel compounds that are designed to be inhibitors of two phases of the life cycle of HIV, an early phase involving reverse transcription (HIV RT inhibitors) and a later phase involving transcriptional HIV gene expression (Tat inhibitors). Compounds chosen for investigation as pro-drugs for HIV RT inhibition are stereochemically defined, novel deoxygenated nucleosides that carry hypermodification in the carbohydrate moiety and those designed as Tat inhibitors are chiral heterocyclic systems belonging to the aminobenzodiazepine family. There is documentation for potent anti-HIV activity for both families of inhibitors. In addition, the rationale for the selection of these compounds for study includes, where relevant, considerations of phosphorylation, cellular stability, bioavailability and host cell toxicity. The synthetic work will involved the development of approaches to both families of compounds so that they could be produced in stereochemically defined, optically pure forms. Characterization including stereochemistry of the final target molecules will be performed by multinuclear NMR spectroscopy, high resolution FAB mass spectrometry, UV and optical activity data, elemental analysis and single crystal X-ray data. Stability studies including the behavior toward selected nucleoside and nucleotide metabolizing enzymes will be investigated. Collaborative antiviral studies of highly purified forms of the target compounds, their derivatives and pro-drug forms will be carried out against HIV-1, HIV-2 and drug-resistant HIV isolates. A number of cell lines will be used in toxicity, on inhibition of HIV-1 p24 Gag protein, on inhibition of HIV RT, on inhibition of proviral DNA synthesis, on inhibition of Tat, and on therapeutic indexes will be determined and analyzed. Cellular combination drug therapeutic studies particularly those involving synergistic inhibition of HIV with antivirally active chiral aminobenzodiazepines (Tat inhibitors) and new or known active nucleosides and nucleotides (HIV RT inhibitors) ar planned. The proposed compounds have a high probability of being antivirally useful and the investigation will contribute to filling some of the gaps in knowledge in this area.