Identification of novel influenza antivirals

新型流感抗病毒药物的鉴定

• 批准号: 8301526
• 负责人: Gregory William Henkel
• 金额: $ 23.34万
• 依托单位: ARISAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301526
• 关键词: Accounting; Adopted; Amantadine resistance; Antiviral Agents; Binding; Biological Assay; C-terminal; Cell-Mediated Cytolysis; Cells; Cessation of life; Collection; Combination Drug Therapy; Complement; Complex; Computer Simulation; Data; Development; Development Plans; Disease Outbreaks; Docking; Doxycycline; Drug resistance; Enzymes; Epidemic; Exhibits; Fluorescence; Fluorescence Resonance Energy Transfer; Genetic Transcription; Health; Hospitalization; Human; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Inhibitory Concentration 50; Institutes; Lactamase; Lead; Libraries; Life; Link; Measures; Modeling; Molecular; Monitor; Mutagenesis; N-terminal; NP protein; Neuraminidase inhibitor; Oseltamivir; Peptide Fragments; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Prevention; Production; Property; Prophylactic treatment; RNA Polymerase I; Reporting; Research; Resistance; Risk; Screening procedure; Seasons; Series; Site; Structure; Testing; Therapeutic; Therapeutic Index; Time; Vaccination; Vaccines; Validation; Variant; Viral; Virus; Virus Diseases; Virus Replication; anti-influenza drug; base; chemical property; combat; cytotoxicity; flu; high throughput screening; influenza outbreak; inhibitor/antagonist; innovation; lead series; novel; pandemic disease; pandemic influenza; pharmacophore; phase 2 study; protein protein interaction; resistant strain; response; scaffold; seasonal influenza; small molecule; small molecule libraries; three dimensional structure; virtual

DESCRIPTION (provided by applicant): The influenza A virus represents one of the greatest global human health risks. Although vaccines provide significant protection from seasonal flu infections they still account for an estimated 36,000 deaths and 200,000 hospitalizations per year in the US alone. Furthermore, the inherent time involved in development, production and distribution of vaccines limits their potential efficacy against rapidly emerging outbreaks. Two classes of drugs have been approved for influenza prophylaxis and treatment. Alarmingly, the past decade has witnessed the emergence of drug resistance as well as recent outbreaks of pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Optimally, as adopted for the treatment of other viral diseases, combination drug therapies would be used to provide the most effective prophylaxis and treatment and to inhibit the emergence of additional drug- resistances. However, only one class of drug (neuraminidase inhibitors) is currently available; amantadine-resistance has become so widespread the amantadanes have become ineffective. There is currently an urgent need for new and more effective therapeutic strategies. Here we provide an innovative approach to identify novel inhibitors of the assembly of the influenza A RNA polymerase subunits PA and PB1. These subunits associate at highly conserved interaction sites through packing of short helical segments. Interestingly, inhibiting PA-PB1 association by mutagenesis or with peptides blocks viral replication and co-crystal structure indicates the binding should be amenable to small- molecule inhibitors. We have developed a novel cell and fluorescence-based PA-PB1 subunit association assay for high-throughput-screening of chemical libraries and confirmation of virtual hit compounds. Using this approach we propose to identify inhibitory compounds acting at a novel influenza A target site for the development of new broad-spectrum influenza drug therapies.

描述（由申请方提供）：甲型流感病毒是全球最大的人类健康风险之一。尽管疫苗提供了对季节性流感感染的显着保护，但仅在美国，它们每年仍造成约36，000人死亡和200，000人住院。此外，疫苗的开发、生产和分发所需的固有时间限制了其对迅速出现的疫情的潜在效力。两类药物已被批准用于预防和治疗流感。令人震惊的是，过去十年出现了抗药性，最近爆发了大流行性（H1N1）和高致病性（H5 N1）甲型流感病毒株。最佳地，如用于治疗其他病毒性疾病，组合药物疗法将用于提供最有效的预防和治疗并抑制额外耐药性的出现。然而，目前只有一类药物（神经氨酸酶抑制剂）是可用的;金刚烷胺耐药性已经变得如此普遍，金刚烷已经变得无效。目前迫切需要新的、更有效的治疗策略。在这里，我们提供了一种创新的方法来确定新的抑制剂的组装流感A RNA聚合酶亚基PA和PB 1。这些亚基通过短螺旋片段的包装在高度保守的相互作用位点处缔合。有趣的是，通过诱变或用肽抑制PA-PB 1缔合阻断病毒复制和共晶体结构表明结合应服从小分子抑制剂。我们开发了一种新的基于细胞和荧光的PA-PB 1亚基缔合测定，用于高通量筛选化学文库和确认虚拟命中化合物。使用这种方法，我们建议确定抑制性化合物作用于一个新的甲型流感病毒的目标网站的发展，新的广谱流感药物治疗。