Exploring alternate targets for inhibition of virus infection by PPI disruption

项目总结/摘要 目前SARS CoV 2的流行是一个严重的提醒，传染病仍然是一个巨大的威胁 人类的福祉和繁荣，呼吸道病毒感染是导致 世界范围内的疾病负担。事实上，考虑到呼吸道病毒的空气传播方式， 迅速和往往最初未被认识到的传播，有可能导致严重的健康问题， 社会和经济影响。尽管医学进步和疫苗接种，许多传染病仍然存在。 在世纪后半叶出现或重新出现。最近发生的病毒性人畜共患病事件， 2009年甲型流感病毒大流行、中东呼吸综合征冠状病毒爆发，以及 当然，正在进行的CoVID 19大流行极大地强调了扩大对这种疾病的基础研究的必要性。 病原体，以开发新的抗病毒疗法，治疗逃逸的可能性低。尽管不断 抑制剂种类多样化的努力，病毒对现有药物的耐药性的反复出现， 常规的抗病毒药物强调了对不太适合治疗逃逸的替代靶点的需要， 特别是非病毒靶，例如促进病毒增殖的宿主细胞因子。 病毒依赖于它们劫持和控制细胞机器的能力来繁殖和传播 生物和人口。因此，抑制病毒与宿主相互作用和重新连接的能力的化合物 细胞机制是宿主导向的抗病毒治疗剂的最有希望的候选物。在这里我们建议 开发一种系统的策略来鉴定病毒-宿主蛋白质-蛋白质相互作用的抑制剂。应用 它的甲型流感病毒，我们将开拓我们的发现管道使用病毒宿主PPI参与贩运， 病毒组分或病毒逃避宿主细胞限制，强烈依赖于病毒组分的过程， 病毒蛋白与宿主因子的相互作用。化学化合物在生物学上破坏- 将使用多参数检测工具包筛选经验证的PPI。经验证的抗病毒潜力 PPI抑制化合物将使用以下甲型流感病毒株测定：

Project Summary/Abstract The current epidemics of SARS CoV2 is an acute reminder that infectious diseases remain an enormous threat to the well-being and prosperity of human populations, and respiratory viral infections are the leading cause of burden of disease world-wide. Indeed, given their airborne mode of transmission, respiratory viruses are prone to rapid and often initially unrecognized spread with potential for pandemics resulting in significant health, societal, and economic impact. Despite medical progress and vaccination, many infectious diseases have emerged or re-emerged in the second half of the twentieth century. Recent events of viral zoonoses such as the influenza A virus 2009 pandemic, the Middle East Respiratory Syndrome (MERS) coronavirus outbreak, and of course the ongoing CoVID19 pandemic dramatically emphasize the need to expand basic research on such pathogens in order to develop new antiviral therapies with low potential for therapeutic escape. Despite constant efforts of diversification of classes of inhibitors, recurrent emergence of viral resistance towards existing conventional antiviral drugs emphasizes the need for alternative targets less amenable to therapeutic escape, especially non-viral targets such as host cellular factors that promote virus multiplication. Viruses depend on their ability to hijack and control the cellular machinery to multiply and spread through organisms and populations. Hence, compounds inhibiting the virus’s ability to interact with, and rewire, the host cellular machinery are the most promising candidates for host-directed anti-viral therapeutics. Here we propose the development of a systematic strategy to identify inhibitors of viral-host protein-protein interactions. Applying it to influenza A viruses, we will pioneer our discovery pipeline using virus-host PPI involved in the trafficking of viral components or in viral escape of host cell restriction, processes that are strongly dependent on the interactions that the viral proteins engage with host factors. Chemical compounds disrupting biologically- validated PPIs will be screened using a multi-parameter toolkit of assays. The anti-viral potential of validated PPI-inhibiting compounds will be determined using influenza A virus strains of