Discovery and development of broad spectrum anti-flaviviral drugs

描述(申请人提供)：节肢动物传播的黄病毒引起一系列重要的人类疾病，目前还没有专门的治疗方法。为了解决在应对这些新出现和重新出现的病毒的准备方面的这一严重不足，这项提议的目标是发现新的药物靶点和开发可广泛用于治疗各种黄病毒感染的新的抗病毒疗法。由四个独立的学术实验室组成的伙伴关系，其中两个在杜克大学，两个在弗吉尼亚大学，将致力于临床前药物开发的关键方面，具体目标如下：(1)确定泛黄病毒疗法的高质量靶标。在这一目标中，将使用三种独立但互补的方法来确定能够治疗各种黄病毒疾病的广谱疗法的细胞靶点。这些措施包括：基因组规模的RNAi筛选以确定黄病毒感染所需的新宿主因子；挖掘人类“嘌呤组”以寻找支持感染的嘌呤结合蛋白；以及应用基于酵母的药物发现平台来识别新的靶点。(2)化学筛选黄病毒复制的抑制剂。将对目标1中确定的目标进行评估，并使用蛋白质组挖掘和基于酵母的方法对一个子集进行小分子文库筛选。将优先考虑具有广谱活性的化合物，包括对蚊媒黄病毒的有效性。(3)用合成孔径雷达(SAR)和药物化学确定PAN抗黄病毒抑制剂。基于AIM 2最具吸引力的筛选产品，将开展多达六个独立的药物化学项目。先导化合物将针对体外结合的效力和组织培养模型的有效性进行优化。(4)临床前试验。已建立的YFV和WNV感染小鼠模型以及新建立的DENV感染模型将用于最大耐受量以及初步的药理和疗效研究。黄病毒是美国公共卫生的一个新威胁，是目前对我们的武装部队和部署在世界各地的其他公民的威胁，也是一个全球性的重大问题。目前，几乎没有办法预防或治疗大多数黄病毒感染，因此开发广谱抗黄病毒药物至关重要。

DESCRIPTION (provided by applicant): Arthropod-borne flaviviruses cause a wide range of important human diseases for which there are no specific therapies. To address this critical shortfall in preparedness to confront these emerging and re-emerging viruses, the goal of this proposal is to discover novel drug targets and develop new antiviral therapies that can be used broadly to treat a variety of flaviviral infections. A partnership of four independent academic laboratories, two at Duke Univeristy and two at the University of Virginia, will attack crucial aspects of pre- clinical drug development, as organized into the following specific aims: (1) Identification of high-quality targets for pan-flaviviral therapeutics. In this aim, three independent yet complementary approaches will be used to identify cellular targets for broad-spectrum therapies capable of treating a diverse group of flaviviral illnesses. These include genome-scale RNAi screens to identify novel host factors required for flaviviral infection, mining of the human "purinome" to find purine-binding proteins that support infection, and application of a yeast-based drug discovery platform for the identification of novel targets. (2) Chemical screens for inhibitors of flavivirus replication. Targets identified in Aim 1 will be evaluated, and a subset will subjected to small molecule library screens using proteome mining and yeast-based methodologies. Priority will be given to compounds showing broad-spectrum activity including efficacy against mosquito-borne flaviviruses. (3) SAR and medicinal chemistry to define pan anti-flaviviral inhibitors. Up to six independent medicinal chemistry programs will be carried forward based on the most attractive products of the screens from Aim 2. Lead compounds will be optimized for potency of in vitro binding and efficacy in tissue culture models. (4) Pre-clinical testing. Established mouse models of YFV and WNV infection and newly established models of DENV infection will be used for maximum tolerated dose and initial pharmacological and efficacy studies. Flaviviruses are an emerging threat to public health in the US, a current risk to our armed forces and other citizens deployed around the world, and a major problem globally. At this time there is little that can be done to prevent or treat the majority of flaviviral infections and therefore development of broad-spectrum anti-flaviviral drugs is of crucial importance.