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Identification and Development of Novel Influenza M2 Inhibitors

新型流感 M2 抑制剂的鉴定和开发

基本信息

批准号：
7455439
负责人：
Benjamin Jacob Doranz
金额：
$ 50万
依托单位：
INTEGRAL MOLECULAR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7455439
关键词：
Abbreviations Adamantane Amantadine Amino Acids Animal Model Animals Behavior Binding Biological Assay Biological Availability Biological Testing Budgets Cardiac Categories Cell-Free System Cells Chemicals Chemistry Complement Cultured Cells Data Analyses Detection Development Diagnostic Direct Costs Dose Drug Delivery Systems Drug Kinetics Drug resistance Equipment Equipment and Supplies Exhibits Face Facilities and Administrative Costs Ferrets Fluorescence Fringe Benefit G-Protein-Coupled Receptors Glass Goals Grant Human Resources In Vitro Influenza Influenza Therapeutic Inpatients Instruction Integral Membrane Protein Ion Channel Ions Lead Left Libraries Life Life Cycle Stages Ligands M2 protein Measures Mediation Methods Modeling Molecular Molecular Biology Molecular Target Monitor Mus Mutation Names Orphan Outpatients Outsourcing Patient Care Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Preclinical Drug Evaluation Predisposition Preparation Prevalence Principal Investigator Property Public Health R43 grant Reagent Research Personnel Research Support Resistance Rimantadine Role Safety Salaries and Fringe Benefits Scientist Screening procedure Side Small Business Innovation Research Grant Structural Models Structure Structure-Activity Relationship Sum System Techniques Technology Testing Therapeutic Time TimeLine Travel United States National Institutes of Health Variant Viral Virus Diseases Virus-like particle Wages Work abstracting anti-influenza base biodefense chemical synthesis chemokine receptor cost cytotoxicity design drug candidate drug withdrawal efficacy testing high throughput screening improved in vivo influenzavirus inhibitor/antagonist miniaturize nanoscale neuronal cell body new technology next generation novel novel strategies novel therapeutics pandemic disease particle pathogen pre-clinical programs public health relevance receptor function safety testing small molecule tool viral resistance voltage gated channel

项目摘要

DESCRIPTION (provided by applicant): Influenza virus is a Category C biodefense pathogen of global public health concern because it causes 3-5 million cases of severe illness every year, and because of the potential for the emergence of new, highly pathogenic strains that could cause pandemic disease. To date, there have been only two successfully-exploited influenza viral drug targets and only four approved drugs. The M2 H+ ion channel has been shown to be necessary for viral infectivity, and suppression of its activity is a well validated anti-viral strategy. The compounds amantadine and rimantadine inhibit M2 and have been used as influenza therapeutics for the past 40 years. However, many currently circulating influenza strains now exhibit resistance to them. New drugs that inhibit M2 via novel mechanisms of interaction therefore have significant potential as influenza therapeutics. However, conventional methods for studying the activity of ion channels are poorly suited to high-throughput screening techniques for identifying new inhibitors. Until now, this has largely precluded the development of new classes of M2 inhibitors. Integral Molecular specializes in developing novel strategies for manipulating and studying integral membrane proteins, including ion channels. We have developed a novel technology for monitoring the activity of M2 that we have shown to be well-suited to high-throughput screening (HTS) applications. Having successfully developed a suitable HTS assay for M2 screening, the current application proposes to use it to identify and develop novel M2 inhibitors.

描述（由申请人提供）：流感病毒是一种C类生物防御病原体，引起全球公共卫生关注，因为它每年导致300万至500万例严重疾病，并且可能出现新的高致病性毒株，可能导致大流行性疾病。迄今为止，只有两种成功开发的流感病毒药物靶标和四种获批药物。M2 H+离子通道已被证明是病毒感染性所必需的，抑制其活性是一种经过充分验证的抗病毒策略。化合物金刚烷胺和金刚乙胺抑制M2，在过去的40年里一直被用作流感治疗剂。然而，许多目前流行的流感病毒株现在对它们表现出耐药性。因此，通过新的相互作用机制抑制M2的新药具有作为流感治疗剂的显著潜力。然而，用于研究离子通道活性的常规方法不太适合用于鉴定新抑制剂的高通量筛选技术。到目前为止，这在很大程度上阻碍了新类型M2抑制剂的开发。Integral Molecular专注于开发操纵和研究膜蛋白（包括离子通道）的新策略。我们已经开发出一种新的技术来监测M2的活性，我们已经证明该技术非常适合高通量筛选（HTS）应用。在成功开发了用于M2筛选的合适HTS测定法之后，本申请提出使用其来鉴定和开发新型M2抑制剂。