BIOCHEMICAL PHARMACOLOGY OF ANTIVIRAL DRUG THERAPY

拟议研究的总体目标仍然是澄清。 药物作用的生化决定因素和药物的发展 治疗病毒感染的协同药物组合。这个 5‘-氨基胸腺嘧啶核苷(5’-AdThd)与病毒和宿主的非特异性相互作用 细胞胸苷激酶提示了几种新的方法，这些方法可能导致 疱疹病毒感染治疗的改进。首先， 反馈性抑制的作用及其可能的拮抗作用 这种调节抗疱疹化合物活性的作用是 建议。5‘-AdThd和其他5’-氨基衍生物的能力 扰乱胸苷激酶活性的调节，从而 增强单纯疱疹病毒中抗病毒核苷的活性 将确定疱疹病毒(HSV)和水痘带状疱疹病毒(VZV)感染的细胞。 其次，5‘-AdThd抑制磷酸化，因此， 三氟代胸苷(CF3dUrd)对单核细胞的毒性。此外, CF3dUrd是一种优秀的人巨细胞病毒(HCMV)抑制剂 体外培养。由于目前还没有有效的体内感染治疗方法， CF3dUrd和5‘-AdThd联合应用选择性抑制 将对HCMV复制进行评估。CF3dUrd的代谢模式 单独和联合5‘-AdThd，将在HCMV感染细胞中 已澄清。第三，根据遗传数据，有人认为 胸苷激酶是干扰素抗病毒的重要决定因素 活动。在某些细胞中，5‘-AdThd可以调节胸苷激酶的活性 一种两阶段的方式。低浓度5‘-AdThd对酶有刺激作用 拮抗胸腺嘧啶核苷三磷酸反馈的活性 抑制力。然而，在较高浓度下，与 胸苷激酶活性部位占优势，活性受到抑制。 这一新的性质表明了一种生物化学方法来评估 胸苷激酶对干扰素活性的影响。使用5‘-AdThd， 将评估干扰素的抗疱疹和抗增殖作用 在对照条件下，刺激和抑制胸腺嘧啶核苷水平 激活酶活性。胸腺嘧啶核苷激酶阳性和阳性的实验 将进行负极电池。这种方法可以提供一种 调节干扰素活性的生化手段。

The overall objectives of the proposed research continue to be elucidation of the biochemical determinants of drug action and the development of synergistic drug combinations for the treatment of viral infections. The unsual interactions between 5'-aminothymidine (5'-AdThd) and viral and host cell thymidine kinases suggest several new approaches which may lead to improvements in the therapy of herpes virus infections. Firstly, elucidation of the role of feedback inhibition and possible antagonism of this effect in regulating the activation of antiherpes compounds is proposed. The ability of 5'-AdThd and other 5'-amino derivatives to disrupt the regulation of thymidine kinase activities and, thereby, to enhance the activation of antiviral nucleosides in herpes simplex virus (HSV) and varicella zoster virus (VZV) infected cells will be determined. Secondly, 5'-AdThd inhibits the phosphorylation and, therefore, the toxicity of trifluorothymidine (CF3dUrd) in unifected cells. In addition, CF3dUrd is an excellent inhibitor of human cytomegalovirus (HCMV) in vitro. Since no effective therapy for this infection in vivo is available, the ability of CF3dUrd and 5'-AdThd, in combination, to selectively inhibit HCMV replication will be assessed. The pattern of CF3dUrd metabolism alone, and in combination with 5'-AdThd, in HCMV infected cells will be elucidated. Thirdly, based on genetic data, it has been suggested that thymidine kinase is an important determinant of interferon's antiviral activity. In some cells 5'-AdThd can modulate thymidine kinase activity in a biphasic manner. At low concentrations 5'-AdThd can stimulate enzyme activity by antagonizing thymidine triphosphate mediated feedback inhibition. At higher concentrations, however, interactions with the active site of thymidine kinase predominate and activity is inhibited. This novel property suggests a biochemical approach to evaluate the influence of thymidine kinase on interferon activity. Using 5'-AdThd, the antiherpes and antiproliferative actions of interferon will be evaluated under conditions of control, stimulated and inhibited levels of thymidine kinase activity. Experiments in both thymidine kinase positive and negative cells will be conducted. This approach could provide a biochemical means of modulating interferon activity.