Using Chemical Biology to Interfere with the Influenza Virus Life Cycle

利用化学生物学干扰流感病毒的生命周期

• 批准号: 8282741
• 负责人: Beatriz MA Fontoura
• 金额: $ 40.11万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282741
• 关键词: Address; Affect; Affinity; Animal Model; Antisense Oligonucleotides; Antiviral Agents; Antiviral Response; Antiviral Therapy; Attenuated; Binding; Biochemical; Biology; Cell Death; Cell Nucleus; Cells; Cellular biology; Chemicals; Complement; Cytoplasm; Drug Delivery Systems; Drug Kinetics; Drug usage; Elements; Family; Gene Expression; Genes; Genetic Epistasis; Growth; Host Defense; Host Defense Mechanism; Human; Immune response; Indium; Infection prevention; Influenza B virus; Interferons; Knowledge; Laboratories; Libraries; Life Cycle Stages; Lung; Measures; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Mus; Mutation; Nuclear; Nuclear Export; PTPN11 gene; Pathogenesis; Pathway interactions; Population; Preclinical Testing; Process; Protein Overexpression; Proteins; RNA Splicing; Resistance; Severity of illness; Signal Transduction; Signal Transduction Pathway; Solubility; Specificity; Staging; Structure; Structure-Activity Relationship; Sum; Synthesis Chemistry; Testing; Therapeutic; Toxic effect; Vaccination; Vesicular stomatitis Indiana virus; Viral; Virulence; Virulence Factors; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; analog; base; cytotoxicity; gene induction; high throughput screening; in vivo; influenza virus INS1 protein; influenza virus strain; influenzavirus; inhibitor/antagonist; insight; mRNA Export; mRNA Precursor; mRNA Stability; mouse model; mutant; novel; novel therapeutics; pharmacophore; positional cloning; prevent; public health relevance; research study; resistance mechanism; response; small molecule; virology; virus pathogenesis

DESCRIPTION (provided by applicant): Many viruses evade host defense mechanisms by targeting specific host vulnerabilities, revealing critical points in host pathways regulating antiviral responses. Recent advances in our understanding of how influenza virus escapes host countermeasures have exposed novel mechanisms of virulence that can be exploited pharmacologically. The NS1 protein of influenza virus, a major virulence factor, inhibits host gene expression and signal transduction required to mount innate and adaptive immune responses. In infected cells, NS1 is localized in the nucleus and the cytoplasm. Based on the function of NS1 as inhibitor of gene expression, we performed a high throughput screen (HTS) of 200,000 synthetic chemical compounds and identified novel inhibitors of NS1. We selected eight classes of novel compounds that significantly restored gene expression in the presence of NS1, and that also inhibited both influenza virus replication and host cell death. We propose that antagonists of either nuclear and/or cytoplasmic activities of NS1 will be novel inhibitors of viral replication and pathogenesis. We will combine chemical biology, cell biology, and virology to investigate the mechanisms by which the compounds we have identified inhibit influenza virus replication. We will characterize two families of small molecules that can serve as leads for molecular therapy. In addition, the proposed studies will provide new insights into mechanisms by which influenza virus evades host defense pathways that can be further targeted pharmacologically. We will pursue the following aims: Aim 1. To investigate structure-activity relationship (SAR) of NS1 inhibitors. Aim 2. To determine the activity of NS1 inhibitors on Antiviral Responses in vivo. Aim 3. To identify targeted pathways and mechanisms of action of compounds which inhibit NS1 function. In sum, these studies will likely reveal novel leads for antiviral therapies as well as provide information on novel mechanisms of viral-host interactions and pathways. PUBLIC HEALTH RELEVANCE: Novel therapeutics to prevent viral disease in humans are needed because viruses become resistant to currently used drugs and it is difficult to protect the entire population by vaccination. This project will develop new classes of chemical compounds capable of inhibiting the growth of influenza virus and other viruses to the stage where they can be shown to prevent viral disease in animal models, the first step towards developing leads to new antiviral therapeutics for humans.

描述（由申请人提供）：许多病毒通过靶向宿主的特定漏洞来逃避宿主的防御机制，揭示宿主调节抗病毒反应途径的关键点。最近我们对流感病毒如何逃避宿主对策的理解取得了进展，揭示了可以在药理学上利用的新的毒力机制。流感病毒的NS1蛋白是一种主要的毒力因子，可抑制宿主先天免疫和适应性免疫应答所需的基因表达和信号转导。在感染细胞中，NS1定位于细胞核和细胞质中。基于NS1作为基因表达抑制剂的功能，我们对20万种合成化合物进行了高通量筛选（HTS），发现了新的NS1抑制剂。我们选择了8类新化合物，它们在NS1存在的情况下显著恢复基因表达，并抑制流感病毒复制和宿主细胞死亡。我们提出NS1核和/或细胞质活性的拮抗剂将成为病毒复制和发病机制的新型抑制剂。我们将结合化学生物学、细胞生物学和病毒学来研究我们已经确定的化合物抑制流感病毒复制的机制。我们将描述两个小分子家族，它们可以作为分子治疗的先导。此外，拟议的研究将为流感病毒逃避宿主防御途径的机制提供新的见解，这些机制可以进一步在药理学上靶向。我们将努力实现以下目标：目标一。探讨NS1抑制剂的构效关系（SAR）。目标2。目的：探讨NS1抑制剂对体内抗病毒反应的影响。目标3。确定抑制NS1功能的化合物的靶向途径和作用机制。总之，这些研究可能会揭示抗病毒治疗的新线索，并提供关于病毒-宿主相互作用和途径的新机制的信息。