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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

项目概要/摘要当前 SARS CoV2 的流行强烈提醒人们，传染病仍然是一个巨大的威胁呼吸道病毒感染是人类福祉和繁荣的主要原因全世界的疾病负担。事实上，鉴于其空气传播方式，呼吸道病毒很容易迅速且往往最初未被认识到的传播，有可能引发大流行病，导致严重的健康问题，社会和经济影响。尽管医疗进步和疫苗接种，许多传染病仍然存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，例如甲型流感病毒 2009 年大流行、中东呼吸综合征 (MERS) 冠状病毒爆发以及当然，正在进行的 CoVID19 大流行极大地强调了扩大此类基础研究的必要性病原体，以开发新的抗病毒疗法，且治疗逃逸的可能性较低。尽管不断抑制剂类别多样化的努力，病毒对现有药物的耐药性反复出现传统的抗病毒药物强调需要寻找不易逃避治疗的替代靶点，尤其是非病毒靶标，例如促进病毒增殖的宿主细胞因子。病毒依赖于劫持和控制细胞机器进行繁殖和传播的能力生物体和种群。因此，抑制病毒与宿主相互作用并重新连接宿主的能力的化合物细胞机制是针对宿主的抗病毒疗法最有希望的候选者。在这里我们建议开发系统策略来识别病毒-宿主蛋白质-蛋白质相互作用的抑制剂。正在申请到甲型流感病毒，我们将利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病毒逃脱宿主细胞限制的过程强烈依赖于病毒蛋白与宿主因子的相互作用。破坏生物的化学化合物- 将使用多参数分析工具包筛选经过验证的 PPI。经验证的抗病毒潜力 PPI 抑制化合物将使用甲型流感病毒株来测定