Accelerating novel countermeasures against RNA viruses through repurposing

鉴于对新的抗病毒策略的巨大需求，一个有效的解决方案是识别被多种病毒劫持的常见宿主因子，并将针对这些因子的批准药物重新用于广谱抗病毒药物。哈特里实验室开发并验证了一种新的生物信息学方法，该方法是有效识别此类候选靶点和抗病毒药物的理想方法。通过整合基因表达数据和药物表达谱的荟萃分析，我们确定了移植排斥反应的可靠信号，并发现了提高移植物存活率的药物。Einav实验室证明了另一种重新调整用途的方法的可行性。我们发现了多种病毒感染性生产的一个致命弱点：需要AP2相关蛋白激酶1(AAK1)和细胞周期蛋白G相关激酶(GAK)，这是调节笼状蛋白适配器蛋白通路的宿主激酶。然后，我们发现了这些靶点的抑制剂，包括批准的抗癌药物；sunifinib和eriotinib，并展示了对丙型肝炎病毒、登革热病毒和艾滋病毒的有效活性。我们假设：1)对多种病毒感染的基因表达谱的荟萃分析可以确定对感染至关重要的常见宿主因素，针对这些因素的已批准药物可以用作广谱抗病毒药物。2)AAK1和GAK抑制剂代表了一类实用的、以宿主为中心的广谱抗病毒药物，对无法治疗的病毒和耐药病毒具有实用价值。在目标1和目标2中，我们将整合基因表达数据集并进行荟萃分析，以确定多种病毒感染中差异表达的宿主因子。将预测可能针对这些宿主因子的现有药物，并确定它们对多个优先药物的抗病毒活性。将进一步开发先导化合物。目标3和4专注于临床前开发具有抗AAKI和GAK活性的批准药物，这些药物已经显示出广谱的抗病毒活性，作为临床阶段产品准备在IND下进行测试。我们将获得支持舒尼替尼和伊洛替尼对抗多种优先病原体感染的适应症的数据集，并使用可用的最佳真实模型来评估这种方法的体内可行性和生物学原理。这些目标将整合分子病毒学、基因组学、生化和药理学方法。该项目将通过建立针对多种NIAID A、B和C类药物的广谱再利用渠道，从以更少的时间和成本确定新产品，到降低2种已经显示出希望的已获批准药物的临床开发风险，为实现多项目中心的目标做出贡献。

In light of the huge unmet need for novel antiviral strategies, an efficient solution is to identify common host factors hijacked by multiple viruses and repurpose approved drugs targeting these factors as broad-spectrum antivirals. The Khatri lab developed and validated a novel bioinformatics approach that is ideal for efficient identification of such candidate targets and antiviral drugs. By integrating meta-analysis of gene expression data and drug expression profiles we identified robust signatures of graft rejection and discovered drugs which improve graft survival. The Einav lab demonstrated feasibility of another repurposing approach. We discovered an Achilles' heel of infectious production of multiple viruses: a requirement for AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK), host kinases that regulate clathrin adaptor proteins pathways. We then discovered inhibitors of these targets, including approved anticancer drugs; sunifinib and eriotinib, and demonstrated potent activity against hepatitis C virus, dengue virus, and HIV. We hypothesize that: 1) meta-analysis of gene expression profiles from multiple viral infections can identify common host factors critical for infection, and approved drugs targeting these factors can be used as broad-spectrum antivirals. 2) AAK1 and GAK inhibitors represent a practical novel, host centered class of broad-spectrum antivirals with utility against viruses for which no treatment is available and resistant viruses. In Aims 1 and 2 we will integrate gene expression data sets and perform meta-analysis to identify differentially expressed host factors across multiple viral infections. Existing drugs that may target these host factors will be predicted and their antiviral activity against multiple priority agents determined. Lead compounds will be further developed. Aims 3 and 4 focus on preclinical development of approved drugs with anti-AAKI and GAK activity, already displaying broad-spectrum antiviral activity, as a clinical stage product ready for testing under an IND. We will obtain data sets supporting indications for sunitinib and eriotinib against infections with multiple priority pathogens and use best available authentic models to assess the in vivo feasibility and biological rationale of this approach. These aims will integrate molecular virology, genomic, biochemical and pharmacological approaches. This project will contribute towards attainment of the multi-project center objectives by establishing a wide-spectrum repurposing pipeline against multiple NIAID Category A, B and C agents, from identifying new products at reduced time and cost to de-risking the clinical development of 2 approved drugs already showing promise.