Effect of Thiopurines on RNA Viruses/Hepatitis C Virus

硫嘌呤对RNA病毒/丙型肝炎病毒的作用

• 批准号: 6672810
• 负责人: ROBERT T STRIKER
• 金额: $ 12.93万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672810
• 关键词: AIDS therapy; DNA directed RNA polymerase; Flaviviridae; RNA virus; adenosine triphosphate; antiAIDS agent; azathioprine; cytotoxicity; guanosine triphosphate; hepatitis C virus; immunopathology chemotherapy; liver cells; microorganism disease chemotherapy; nucleoside analog; nucleoside inhibitor; pharmacokinetics; polymerase chain reaction; replicon; ribavirin; ribonucleosides; thin layer chromatography; thiopurine; tissue /cell culture; virus replication

DESCRIPTION (provided by applicant): Viruses from the Family Flaviviridae, including West Nile Virus, Dengue Virus and Hepatitis C Virus (HCV), are significant causes of morbidity and mortality, yet have few to no treatment options. Deoxyribonucleoside analogs form an important part of antiviral therapy for human immunodeficiency virus (HIV), but ribonucleoside analogs have been relatively unstudied for their potential to affect HCV or RNA viruses in general. We have determined conditions in which thiopurine nucleoside analogs inhibit a model Flaviviridae, Bovine Viral Diarrhea Virus (BVDV), in cell culture without cytotoxicity. Ribavirin, another purine analog, increases the efficacy of interferon treatment. Multiple mechanisms have been proposed for how ribavirin may act, but it remains unclear which mechanism(s) predominant. HCV positive transplant patients are often exposed to long-term immunosuppressive agents including thiopurines that also alter purine metabolism. Since these drugs share some, but not all of the mechanistic options for ribavirin, we will compare the effect of each on viral replication. The goal of this proposal is to extend these findings to HCV and determine the mechanism of action. Thiopurines will be tested for antiviral effect on the HCV replicon, and if they exert selective pressure on viral polymerases. Thiopurines will be tested for recognition, and utilization by the HCV and BVDV polymerase, which will aid us in designing more potent nucleosides. Finally we will further define the mechanism of this inhibition by looking at the size of purine pools and the effect of altering thiopurine metabolism on thiopurine's antiviral capacity. This proposal will determine the relative direct and indirect effect of thiopurines on RNA viral replication and the implications of that effect for the treatment of HCV patients with related purines such as ribavirin.

描述（由申请人提供）：来自Flaviviridae的病毒，包括西尼罗河病毒，登革热病毒和乙型肝炎病毒（HCV），是发病率和死亡率的重大原因，但几乎没有治疗选择。脱氧核糖核苷类似物构成了人类免疫缺陷病毒（HIV）抗病毒疗法的重要组成部分，但是核糖核苷类似物的一般潜在影响HCV或RNA病毒的潜力是相对未研究的。我们确定了硫嘌呤核苷类似物在没有细胞毒性的细胞培养中抑制模型Flaviviridae，牛病毒腹泻病毒（BVDV）。另一种嘌呤类似物利巴韦林提高了干扰素治疗的功效。已经提出了关于利巴韦林如何作用的多种机制，但尚不清楚哪种机制主要是主导。 HCV阳性移植患者通常会接触长期免疫抑制剂，包括硫嘌呤也会改变嘌呤代谢。由于这些药物具有利巴韦林的一些机械选择，但我们将比较每种药物对病毒复制的影响。该提案的目的是将这些发现扩展到HCV并确定作用机理。硫嘌呤将测试对HCV复制子的抗病毒作用，如果它们对病毒聚合酶施加选择性压力。硫嘌呤将通过HCV和BVDV聚合酶进行识别和利用，这将有助于我们设计更多有效的核苷。最后，我们将通过查看嘌呤池的大小以及改变硫嘌呤代谢对硫嘌呤抗病毒能力的影响进一步定义这种抑制的机制。该提案将确定硫嘌呤对RNA病毒复制的相对直接和间接作用，以及该作用对治疗HCV患者（如利巴韦林）的治疗的影响。