Identification and Development of Novel Influenza 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。

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.