Host-targeted antivirals for influenza and other respiratory virus infections

描述(申请人提供)：目前市场上的抗病毒药物是根据所谓的“一种细菌，一种药物”策略开发的。也就是说，每种药物对一种特定的病毒都是高度特异的。相比之下，广谱抗生素的开发使细菌感染的治疗发生了革命性的变化，广谱抗生素可以作用于多种细菌。这项提案旨在通过发现抗病毒药物来对病毒感染做同样的事情 具有广谱抗呼吸道病毒活性的化合物。这种药物的优点是：1)在开始治疗之前，不需要正确诊断病毒感染的原因。2)治疗由对当前药物具有抗药性的病毒引起的感染的能力。3)治疗由病毒引起的感染的能力，而这些病毒没有特效药。在R21阶段，目标是确定有效生长流感病毒和其他呼吸道病毒所需的细胞因子，以及具有合适的可用药特性的细胞因子。候选者将通过一个过程进行选择，该过程涉及整合包含关于流感病毒与宿主细胞相互作用的RNAi、蛋白质组和转录组信息的多个数据集。那些对角色有最好支持的可下药的宿主因素 在促进流感病毒复制方面，将进行进一步的验证，并将评估其与其他呼吸道病毒的类似作用。将优先考虑最广泛的病毒所需的那些因素。将选择三个细胞靶点进入R33阶段，在该阶段将进行小分子高通量筛选以识别特定的抑制剂。这些宿主因子抑制剂的特征将是它们抑制多种呼吸道病毒的能力，最有效的将在动物模型中分析抗病毒效果。通过仔细选择得到良好支持的宿主靶标，这项提议旨在确定具有广谱抗病毒活性的先导化合物。

Description (as provided by the applicant): Antiviral drugs on the market today have been developed according to the so-called "one bug, one drug" strategy. That is, each drug is highly specific for a particular virus. In contrast, treatment of bacterial infections has been revolutionized by the development of broad-spectrum antibiotics, which can act on multiple bacteria. This proposal aims to do the same for virus infections through the discovery of antiviral compounds with broad-spectrum activities against respiratory viruses. The advantages to such drugs are: 1) Eliminating the need to correctly diagnose the cause of the virus infection prior to commencing treatment. 2) The ability to treat infections caused by viruses that are resistant to current drugs. 3) The ability to treat infections caused by viruses for which no specific drugs exist. In the R21 phase the goal is to identify cellular factors that are required for efficient grwth of influenza virus and other respiratory viruses and which possess suitable druggable properties. Candidates will be selected via a process that involves integration of multiple datasets containing RNAi, proteomic and transcriptome information on the interaction of influenza virus with host cells. Those druggable host factors that have the best support for a role in promoting influenza virus replication will undergo further validation and will be assessed for similar roles with other respiratory viruses. Priority will be given to those factors required by te broadest range of viruses. Three cellular targets will be chosen to enter the R33 phase, where small molecule high-throughput screens will be performed to identify specific inhibitors. These host factor inhibitors will be characterized for their ability to inhibit multiple respiratory virues and the most potent will be analyzed for antiviral efficacy in animal models. Through careful selection of well-supported host targets, this proposal aims to identify lead compounds with broad-spectrum antiviral activity.