Exploring alternate targets for inhibition of virus infection by PPI disruption

项目摘要/摘要 目前SARS CoV2的流行是一个尖锐的提醒，传染病仍然是一个巨大的威胁 对人类的福祉和繁荣来说，呼吸道病毒感染是 全世界的疾病负担。事实上，鉴于呼吸道病毒在空气中的传播方式，它们很容易 到最初往往未被发现的快速传播，有可能导致大流行，导致重大健康问题， 对社会和经济的影响。尽管医学进步和接种疫苗，但许多传染病已经 在二十世纪下半叶出现或重新出现。最近发生的病毒性人畜共患病事件，如 2009年甲型流感病毒大流行、中东呼吸综合征冠状病毒爆发和 当然，正在进行的CoVID19大流行极大地强调了扩大对这些疾病的基础研究的必要性 病原体，以开发低潜在治疗逃逸的新的抗病毒疗法。尽管不变 努力使抑制剂种类多样化，反复出现对现有病毒的耐药性 传统的抗病毒药物强调有必要寻找不太容易逃脱治疗的替代靶点， 尤其是非病毒靶标，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 有机体和种群。因此，抑制病毒与宿主相互作用并重新连接宿主能力的化合物 细胞机械是宿主导向抗病毒疗法最有前途的候选药物。在这里，我们建议 确定病毒-宿主蛋白-蛋白质相互作用的抑制物的系统策略的发展。施药 它对甲型流感病毒，我们将开创我们的发现管道使用病毒宿主PPI参与贩运 病毒成分或在病毒逃避宿主细胞限制的过程中，强烈依赖于 病毒蛋白与宿主因子的相互作用。会破坏生物的化合物- 验证的PPI将使用多参数分析工具包进行筛选。经验证的抗病毒潜力 将使用甲型流感病毒株确定PPI抑制化合物

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