Identification of Novel Influenza Inhibitors

描述(申请人提供)：流感病毒是全球公共卫生关注的C类生物防御性病原体，因为它每年导致300-500万例严重疾病，而且可能出现新的高致病性毒株，可能导致大流行疾病。迄今为止，只有两种成功开发的流感药物靶标，只有四种获得批准的药物。M2 H+离子通道已被证明是病毒感染性所必需的，抑制其活性是一种得到充分验证的抗病毒策略。金刚烷胺和金刚乙胺化合物抑制M2，在过去的40年里一直被用作流感治疗药物。然而，目前流行的许多流感病毒株现在对它们表现出抗药性。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药物的巨大潜力。然而，研究离子通道活性的传统方法不太适合用于识别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型M2抑制剂的开发。整体式分子公司专门开发用于操作和研究整体膜蛋白(包括离子通道)的新策略。我们已经开发了一种用于监测M2活性的新技术，我们已经证明该技术非常适合高通量筛选(HTS)应用。在成功开发了一种适合M2筛选的HTS方法后，目前的应用建议使用它来识别和开发新的M2抑制剂。与公共卫生相关：这种SBIR将产生的产品是一种新型的流感小分子抑制剂。这项提案中开发的抑制剂将针对一个经过验证的流感分子靶标M2，并克服金刚烷类药物面临的主要障碍，因为将筛选化合物对一些M2变种的效力，以最大限度地增加开发广谱流感抑制剂的机会。M2对流感的生命周期至关重要，这表明下一代M2活性抑制剂具有巨大的治疗潜力。

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 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. PUBLIC HEALTH RELEVANCE: The product that will result from this SBIR is a novel small molecule inhibitor of influenza. The inhibitors developed in this proposal will target a validated influenza molecular target, M2, and overcome the major obstacles faced by the adamantane drugs because compounds will be screened for potency against a number of M2 variants to maximize the chances of developing a broad-spectrum influenza inhibitor. M2 is critical to the influenza life-cycle, suggesting there is substantial therapeutic potential for next-generation inhibitors of M2 activity.