Exploring alternate targets for inhibition of virus infection by PPI disruption

探索通过 PPI 破坏抑制病毒感染的替代靶点

基本信息

批准号：
10217383
负责人：
Michael A Calderwood
金额：
$ 20.16万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-22 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217383
关键词：
Acute Adherence Advanced Development Affect Amino Acids Antiviral Agents Antiviral Therapy Area Basic Science Binding Binding Sites Biological Biological Assay COVID-19 pandemic Cell physiology Cells Chemicals Communicable Diseases Development Disease Outbreaks Drug Targeting Effectiveness Event Exhibits Genetic Genome Health Hot Spot Human Infection Influenza A virus Integration Host Factors Libraries Life Cycle Stages Ligand Binding Medical Middle East Respiratory Syndrome Coronavirus Molecular Conformation Nature Organism Personal Satisfaction Pharmaceutical Preparations Phenotype Population Process Property Proteins Proteome Recurrence Resistance Testing Therapeutic Vaccination Validation Viral Viral Proteins Viral Respiratory Tract Infection Virus Virus Diseases Virus Inhibitors Virus Replication Zoonoses base burden of illness economic impact inhibitor/antagonist innovation obligate intracellular parasite pandemic disease pathogen prevent protein protein interaction prototype respiratory virus screening small molecule therapeutically effective trafficking transmission process viral resistance

项目摘要

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

项目摘要/摘要 SARS COV2的当前情节是一个急性提醒，传染病仍然是巨大的威胁人群的幸福和繁荣以及呼吸道病毒感染是主要原因全球疾病负担。确实，鉴于其空中传播方式，呼吸道病毒易于快速且通常是最初无法识别的蔓延，并可能导致大流行，从而带来重要的健康状况，社会和经济影响。尽管医疗进展和疫苗接种，但许多传染病仍有在20世纪下半叶出现或重新出现。病毒动物的最新事件，例如流感病毒2009年大流行，中东呼吸道综合征（MERS）冠状病毒爆发和当然，持续的Covid19大流行极大地强调了扩大基础研究的必要性病原体以开发具有较低疗法逃脱潜力的新抗病毒疗法。尽管恒定抑制剂类别多样化的努力，对现有病毒抗性的反复出现常规的抗病毒药物强调需要对替代靶标的进行治疗的逃生，特别是非病毒靶标，例如促进病毒繁殖的宿主细胞因子。病毒取决于其劫持和控制蜂窝机械的能力，以繁殖并传播有机体和种群。因此，化合物抑制病毒与宿主互动和重新连接的能力细胞机械是宿主指导的抗病毒疗法的最有希望的候选者。我们在这里提出制定系统策略以鉴定病毒宿主蛋白 - 蛋白质相互作用的抑制剂。申请为了影响扎病病毒，我们将使用参与贩运的病毒宿主PPI开拓我们的发现管道病毒成分或宿主细胞限制的病毒逃生，强烈依赖于该过程病毒蛋白与宿主因素相关的相互作用。化合物在生物学上破坏经过验证的PPI将使用多参数工具包进行筛选。验证的抗病毒潜力抑制PPI抑制化合物将使用影响