Identification and Characterization of Novel Flavivirus Antivirals

新型黄病毒抗病毒药物的鉴定和表征

基本信息

批准号：
7649815
负责人：
Nigel Bourne
金额：
$ 27.15万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2009-02-28
项目状态：
已结题

项目摘要

Flaviviruses are the causative agents of a number of diseases of public health importance including West Nile encephalitis, yellow fever, dengue fever and Japanese encephalitis. However, current treatment options for these diseases are limited and there is a real need for new antiviral agents with specific activity against these viruses. The long-term objectives of this project are to meet this need by identifying and characterizing new small molecule compounds with broad spectrum activity against medically important f1aviviruses. The project that we propose has three specific aims. Specific Aim 1: High Throughput Screening Identification of Novel Lead Compounds. Using a West Nile virus (WNV) virus-like particle (VLP) assay that we have developed and, which is suitable for use under low bio-containment conditions we will conduct high-throughput screening of a large library of compounds at the National Screening Laboratory for the Regional Centers of Excellence. The data generated during screening will be analyzed and the most promising antiviral compounds identified. The activity of the selected compounds against WNV will be confirmed using live virus assays and, their broad spectrum anti-flavivirus activity determined in live virus assays with dengue virus and yellow fever virus. Specific Aim 2: Medicinal Chemistry Modification and Iterative in vitro Antiviral Testing. Based on their activity against all three flaviviruses, toxicity profiles and potential for chemical modification, three compounds will be identified as leads and will undergo a series of medicinal chemical modifications in the Parallel Synthesis and Medicinal Chemistry facility at UTMB. Each round of chemical modifications will involve the synthesis of a small number of compounds which will then undergo rapid in vitro toxicity and antiviral activity testing in live virus assays. This process will result in several rounds of controlled iterative synthesis and evaluation that we expect will lead to the identification of more potent antiviral compounds. Specific Aim 3: In Vivo Evaluation of Activity in a Small Animal Model of WNV Encephalitis In this aim the two most promising compounds identified during the chemical modification studies will be evaluated for activity in vivo using a mouse model of WNV encephalitis. Thus by the end of the project period we expect to have identified a number of new compounds with broad spectrum activity against medically important flaviviruses and to have undertaken preliminary studies to evaluate their potential therapeutic utility in a well defined animal model with virologic and pathologic endpoints that are relevant to those seen in the clinical situation.

黄病毒是多种公共卫生重要性疾病（包括西部）的原因尼罗河脑炎，黄热病，登革热和日本脑炎。但是，当前的治疗选择因为这些疾病是有限的，并且真正需要具有特定活性的新抗病毒药这些病毒。该项目的长期目标是通过识别和表征来满足这一需求针对医学上重要的F1Avivivires的新型小分子化合物具有广泛活性。这我们建议的项目具有三个具体目标。特定目标1：新型铅化合物的高吞吐量筛选鉴定。使用我们已经开发的西尼罗河病毒（WNV）病毒样颗粒（VLP）测定法为了在低生物接触条件下使用，我们将对大型库进行高通量筛选国家筛查实验室的卓越中心的化合物。数据将分析在筛查过程中产生的，并确定最有希望的抗病毒化合物。这所选化合物对WNV的活性将使用实时病毒测定法进行确认，并且它们的广泛在登革热病毒和黄热病病毒的实时病毒测定中确定的频谱抗氟病毒活性。具体目标2：药物化学修饰和体外抗病毒测试。根据它们对所有三种黄病毒的活性，毒性特征和化学修饰的潜力，三种化合物将被识别为铅，并将在 UTMB的平行合成和药物化学设施。每一轮化学修饰将涉及少数化合物的合成，然后将经历快速的体外毒性和活病毒测定中的抗病毒活性测试。这个过程将导致几轮受控的迭代我们期望的合成和评估将导致鉴定更有效的抗病毒化合物。特定目的3：在WNV脑炎的小动物模型中对活动的体内评估在这个目标中，化学修饰研究中确定的两种最有前途的化合物将是使用WNV脑炎的小鼠模型在体内评估活性。因此，到项目期结束时，我们希望已经确定了许多新化合物针对医学上重要的黄病毒的频谱活动，并进行了初步研究在具有病毒学和病理学的明确的动物模型中评估其潜在的治疗效用与在临床情况下看到的终点相关。