Identification of novel influenza antivirals

新型流感抗病毒药物的鉴定

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：流感A病毒代表着全球最大的人类健康风险之一。尽管疫苗可为季节性流感感染提供了重大保护，但仅在美国，每年仍会估计每年36,000例死亡和20万例住院。此外，疫苗的开发，生产和分布涉及的固有时间限制了它们的潜在功效，以避免快速出现的暴发。两类药物已被批准用于预防流感和治疗。令人震惊的是，过去十年见证了耐药性的出现以及最近大流行（H1N1）和高度致病性（H5N1）菌株的流感A. A.的最佳菌株，这是针对其他病毒疾病的治疗所采用的，结合药物疗法将是合并药物疗法的。用于提供最有效的预防和治疗，并抑制额外耐药性的出现。但是，目前只有一类药物（神经氨酸酶抑制剂）。阿曼达丁抗性已经变得如此普遍，因为阿曼塔丹人已经无效。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鉴定流感A型RNA聚合酶亚基PA和PB1组装的新型抑制剂。这些亚基通过短螺旋段的包装在高度保守的相互作用位置关联。有趣的是，通过诱变或与肽阻断病毒复制和共晶结构的抑制PA-PB1的关联表明，结合应适合小分子抑制剂。我们已经开发了一种新型的基于荧光的细胞和基于荧光的PA-PB1亚基结合测定法，用于对化学文库进行高通量筛查和虚拟命中化合物的确认。使用这种方法，我们建议鉴定在新型流感上作用起作用的抑制性化合物，这是开发新的广谱流感药物疗法的目标位点。