Accelerating novel countermeasures against RNA viruses through repurposing

通过重新利用加速针对 RNA 病毒的新对策

• 批准号: 9631966
• 负责人: Shirit Einav
• 金额: $ 66.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9631966
• 关键词: Adaptor Signaling Protein; Affinity; Antineoplastic Agents; Antiviral Agents; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Categories; Clathrin Adaptors; Clinic; Clinical; Clinical Trials; Dasatinib; Data; Data Set; Databases; Dengue Virus; Development; Drug Combinations; Drug Targeting; Enzymes; Expression Profiling; Future; GAK gene; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Graft Rejection; Graft Survival; HIV; Health; Hepatitis C virus; Human; In Vitro; Individual; Infection; Infectious hepatitides; Integration Host Factors; Lead; Light; Manuscripts; Maps; Measurement; Medical Records; Meta-Analysis; Methods; Modeling; Molecular; Molecular Target; Molecular Virology; Mus; National Institute of Allergy and Infectious Disease; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphotransferases; Production; Protein Kinase; Proteins; Publishing; RNA; RNA Viruses; Resistance; Testing; Therapeutic; Time; Transcription Factor AP-2 Alpha; Viral; Virus; Virus Diseases; adeno-associated viral vector; anti-cancer; anti-viral efficacy; atorvastatin; clinical development; clinical risk; combat; cost; design; differential expression; high throughput analysis; improved; in vivo; inhibitor/antagonist; kinase inhibitor; mouse model; novel; overexpression; pathogen; pharmacodynamic biomarker; preclinical development; tissue culture; viral resistance; virus host interaction

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.

鉴于对新型抗病毒策略的巨大需求尚未得到满足，一种有效的解决方案是识别被多种病毒劫持的共同宿主因子，并将已批准的药物靶向这些因子作为广谱抗病毒药物。Khatri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，我们确定了移植物排斥反应的强大特征，并发现了改善移植物存活的药物。Einav实验室展示了另一种重新利用方法的可行性。我们发现了多种病毒感染性生产的致命弱点：对ap2相关蛋白激酶1 （AAK1）和细胞周期蛋白g相关激酶（GAK）的需求，这两种宿主激酶调节网格蛋白衔接蛋白途径。然后我们发现了这些靶点的抑制剂，包括批准的抗癌药物；舒尼尼和厄替尼，并证明对丙型肝炎病毒，登革热病毒和艾滋病毒的有效活性。我们的假设是：1)对多种病毒感染的基因表达谱进行荟萃分析，可以识别出对感染至关重要的共同宿主因子，并且已批准的靶向这些因子的药物可以用作广谱抗病毒药物。2) AAK1和GAK抑制剂代表了一种实用的新型、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效用。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。现有药物可能针对这些宿主因子进行预测，并确定其对多种优先药物的抗病毒活性。先导化合物将进一步开发。目标3和目标4侧重于临床前开发具有抗aaki和GAK活性的获批药物，这些药物已经显示出广谱抗病毒活性，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依替尼治疗多种优先病原体感染的适应症的数据集，并使用最佳可用的真实模型来评估该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、生物化学和药理学方法。该项目将有助于实现多项目中心的目标，通过建立针对多种NIAID a、B和C类药物的广谱再利用管道，从减少时间和成本的新产品识别到降低两种已获批准的药物的临床开发风险，已经显示出希望。