Identification and Characterization of Novel Flavivirus Antivirals

新型黄病毒抗病毒药物的鉴定和表征

• 批准号: 7676476
• 负责人: Nigel Bourne
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676476
• 关键词: Address; Affect; Alphavirus; Antiviral Agents; Attenuated; Back; Biological Assay; Boston; Categories; Cells; Chemicals; Clinical; Combined Modality Therapy; Containment; Data; Dengue; Dengue Virus; Development; Diagnostic; Disease; Dose; Emerging Communicable Diseases; Encephalitis; Evaluation; Family; Flavivirus; Flavivirus Infections; Frequencies; Funding; Future; Goals; In Vitro; Infection; Laboratories; Lead; Life; Modeling; Modification; Mutation; National Institute of Allergy and Infectious Disease; Orthobunyavirus; Outcome; Pharmaceutical Chemistry; Process; Program Development; Public Health; RNA Viruses; Replicon; Reporter Genes; Resistance; Resistance development; Rift Valley Fever; Rift Valley fever virus; Screening procedure; Series; Splenomegaly; Symptoms; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Vaccines; Venezuelan Equine Encephalitis Virus; Venezuelan Equine Encephalomyelitis; Viral; Viremia; Virion; Virus; Virus Replication; West Nile virus; base; biodefense; chikungunya; drug discovery; experience; feeding; high throughput screening; improved; in vitro activity; in vivo; interest; meetings; member; mouse model; mutant; novel; novel therapeutics; particle; pathogen; practical application; programs; resistance mechanism; response; small molecule; therapeutic vaccine

RNA viruses cause a variety of emerging and biodefense-related diseases of public health importance. The viruses come from multiple families, and the diseases they cause are diverse. They include West Nile encephalitis and dengue fever both caused by flaviviruses, Venezuelan equine encephalitis and chikungunya caused by alphaviruses and Rift Valley fever caused by a bunyavirus. Current therapies for these diseases are limited, and there is a real need to develop effective small molecule antiviral agents. The central objectives of this five year project are to meet this need by identifying and developing new antivirals with activity against medically important RNA viruses giving particular emphasis to broadly active candidates. In aim 1 we will develop compounds active against flaviviruses from diverse chemical leads identified by high throughput screening (HTS) using a West Nile virus virus-replicon particle (VRP) assay that can be used under low biocontainment conditions. The compounds will undergo an iterative program with multiple rounds of chemical modifications, and in vitro toxicity and antiviral activity testing against flaviviruses that will result in the identification of improved antivirals. In aim 2 we will develop an alphavirus VRP assay into a HTS-suitable format and use this assay to screen for lead compounds that will then be used to initiate an alphavirus antiviral discovery and development program using the paradigm described in aim 1. In aim 3 we will develop an HTS assay that utilizes an attenuated Rift Valley fever virus that expresses a reporter gene to initiate a bunyavirus antiviral program. In each aim activity will be evaluated using multiple viruses within the family, to identify compounds with broad activity. This process will be continued by evaluating active compounds against members of the other virus families of interest. In doing this we recognize that the early clinical signs caused by many of these viruses are difficult to distinguish; thus, broad spectrum antivirals that could be used early in infection when they would have the best chance of clinical impact are a clinical priority. Concomitant with the drug discovery studies, in aim 4 we will explore the mechanism of action of compounds, generate resistant mutations to define the frequency with which they occur, and determine the mechanism of resistance. In addition, we will explore the effects of using active compounds in combination, in attempts to identify synergistic combinations with potential future clinical utility. Finally in aim 5 we will evaluate two promising compounds in vivo in mouse models of flavivirus diseases.

RNA病毒会导致各种与公共健康重要性的新兴和生物反应有关的疾病。这 病毒来自多个家庭，它们引起的疾病多种多样。他们包括西尼罗河 脑炎和登革热是由黄病毒，委内瑞拉马脑炎和基孔肯尼亚引起的 由甲状腺病毒引起的α病毒和裂谷发烧引起。这些疾病的当前疗法 有限，真正需要开发有效的小分子抗病毒药。中央 这个五年项目的目标是通过与 针对医学上重要的RNA病毒的活性特别强调了广泛活跃的候选者。 在AIM 1中，我们将开发出对黄病毒的活跃化合物，从 使用西尼罗河病毒病毒 - 修复子粒子（VRP）测定法的高吞吐量筛查（HTS） 在较低的生物内在条件下使用。这些化合物将经历具有多个的迭代程序 化学修饰的一轮，体外毒性和抗病毒活性测试，针对黄病毒 导致鉴定改善的抗病毒药。在AIM 2中，我们将将Alphavirus VRP分析开发到一个 HTS适合格式，并使用此测定法筛选铅化合物，然后将其用于启动 α病毒抗病毒发现和开发计划使用AIM 1中描述的范式。在AIM 3中我们 将开发一种HTS测定法，该测定法使用衰减的裂谷谷热病毒，该病毒表达了记者基因 启动Bunyavirus抗病毒计划。在每个目标活动中，将使用多种病毒评估 家庭，确定具有广泛活性的化合物。通过评估活动将继续此过程 针对其他感兴趣的病毒家族的化合物。为此，我们认识到早期 许多这些病毒引起的临床体征很难区分。因此，广泛的抗病毒药 当它们具有最佳临床影响的最佳机会是临床时，可以在感染的早期使用 优先事项。与药物发现研究同时，在AIM 4中，我们将探讨 化合物，产生抗性突变以定义其发生的频率，并确定 抗性机制。此外，我们将探讨使用活性化合物组合的效果， 试图确定与潜在的未来临床实用程序的协同组合。终于在目标5中我们会 在黄病毒疾病的小鼠模型中评估体内两种有希望的化合物。