Pan-Influenza virus inhibitors: Small molecules that disrupt host ADAR1-viral NS1 interactions

泛流感病毒抑制剂：破坏宿主 ADAR1-病毒 NS1 相互作用的小分子

基本信息

批准号：
9086232
负责人：
Balaji Manicassamy
金额：
$ 19.33万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086232
关键词：
ADAR1 Age Antiviral Agents Back Biological Assay Cells Data Deaminase Development Double-Stranded RNA Drug Kinetics Ensure Epidemic Evaluation Evaluation Studies Future Goals Half-Life Health Herd Immunity Human In Vitro Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Influenza Therapeutic Integration Host Factors Lead Libraries Liver Microsomes Luciferases Maintenance Measures Methods Microsomes Morbidity - disease rate Mus Mutation Permeability Pharmaceutical Preparations Phase Preclinical Testing Process Production Property RNA Editing Reporter Resistance Staging Structural Genes Structure System Testing Therapeutic Toxic effect Treatment Efficacy Vaccination Vaccines Validation Viral Virus Virus Diseases Virus Inhibitors Virus Replication adenosine deaminase alternative treatment analog base combat cytotoxicity fitness high throughput screening improved in vitro activity in vivo indexing influenza virus strain influenza virus vaccine influenzavirus inhibitor/antagonist interest mortality mouse model novel pandemic disease pre-clinical preclinical evaluation public health relevance research study resistance mutation resistant strain seasonal influenza small molecule small molecule inhibitor viral resistance

项目摘要

DESCRIPTION (provided by applicant): Influenza A viruses pose a serious threat to human health, causing seasonal epidemics and occasional pandemics that result in significant morbidity and mortality worldwide. The most effective method of protection against seasonal influenza virus is vaccination; however, vaccines are ineffective against novel influenza viruses, as there is little or no cross protection afforded by seasonal vaccines. Because production of sufficient quantities of influenza vaccine requires at least 6 months, and establishment of herd immunity is a lengthy and complicated process, people of all ages are highly vulnerable to novel influenza virus strains. To overcome the limitations of the available influenza vaccines, small molecule inhibitors are still a vital need as an alternative treatment to influenza virus infection Unfortunately, resistance has rendered existing therapeutics much less effective, and the need remains for new antiviral drugs to combat future epidemics and pandemics. We have recently identified Adenosine Deaminase Acting on double stranded RNA (ADAR1) as a host factor critical to the replication of multiple strains of influenza viruses. Importantly, we have determind that the non- structural protein 1 (NS1) of influenza virus interacts with ADAR1 and enhances its RNA editing activity, which is necessary for efficient viral replication and maintenance of progeny fitness. Our data demonstrates that influenza virus replication is reduced 10-1000 fold in cells lacking ADAR1 or cells expressing a catalytically inactive ADAR1; furthermore, viruses passaged in the absence of ADAR1 fail to acquire resistance mutations. We have developed a luciferase-based assay to measure the deaminase activity of ADAR1 and have validated its robustness in the high throughput screening (HTS) system. We will screen for small molecule inhibitors that disrupt ADAR1-NS1 interactions and/or directly inhibit ADAR1 deaminase activity, improve the potency and selectivity of identified compounds by SAR studies, perform preclinical evaluation studies in mice with influenza viruses, and develop advanced lead compounds suitable for further preclinical testing.

描述（由申请人提供）：甲型流感病毒对人类健康构成严重威胁，引起季节性流行病和偶尔的大流行，导致全球范围内显着的发病率和死亡率。然而，预防季节性流感病毒的最有效方法是疫苗接种。流感疫苗对新型流感病毒无效，因为季节性疫苗几乎没有或根本没有交叉保护作用。因为生产足够数量的流感疫苗至少需要6个月，而建立群体免疫是一个漫长而复杂的过程，所有年龄段的人都需要接种疫苗。高度易受新型流感病毒株的影响，为了克服现有流感疫苗的局限性，小分子抑制剂作为流感病毒感染的替代治疗方法仍然是至关重要的，耐药性使现有疗法的效果大大降低，并且仍然需要新的抗病毒药物。我们最近发现作用于双链RNA的腺苷脱氨酶（ADAR1）是对多种流感病毒株复制至关重要的宿主因子。流感病毒的蛋白 1 (NS1) 与 ADAR1 相互作用并增强其 RNA 编辑活性，这对于病毒复制和维持后代健康是必需的。我们的数据表明，在缺乏 ADAR1 或表达催化的细胞中，流感病毒复制有效倍数减少。 ADAR1 失活；此外，在缺乏 ADAR1 的情况下传代的病毒无法获得抗性突变。我们开发了一种基于荧光素酶的测定法来测量 ADAR1 的脱氨酶活性。 ADAR1 并已在高通量筛选 (HTS) 系统中验证了其稳健性。我们将筛选破坏 ADAR1-NS1 相互作用和/或直接抑制 ADAR1 脱氨酶活性的小分子抑制剂，通过 SAR 研究提高已识别化合物的效力和选择性。在感染流感病毒的小鼠中进行临床前评估研究，并开发适合进一步临床前测试的先进先导化合物。