Development of novel broad-spectrum influenza A inhibitors

说明(申请人提供)：甲型流感病毒是全球最大的人类健康风险之一。尽管疫苗提供了对季节性流感感染的显著保护，但仅在美国，它们每年仍造成约3.6万人死亡和20万人住院。此外，疫苗的开发、生产和分发所涉及的固有时间限制了它们对迅速出现的疫情的潜在效力。两类药物已被批准用于预防和治疗流感。令人震惊的是，在过去的十年里，出现了抗药性以及2009年大流行(H1N1)和高致病性(H5N1)新型甲型流感病毒株。金刚烷胺抗药性变得如此普遍，以至于金刚烷胺几乎无效，一些流感毒株已经对神经氨酸酶抑制剂表现出显著的抗药性。与其他病毒疾病的治疗一样，最好的办法是使用联合药物疗法来提供最有效的预防和治疗，并抑制出现更多的抗药性。因此，迫切需要新的、更有效的抗病毒单一疗法和联合疗法。在这里，我们提供了一种创新的方法来识别金刚烷胺敏感和耐药形式的M2质子通道的抑制剂，以提供新的广谱疗法。使用这种方法，我们提供了一个平台，用于鉴定作用于临床验证的甲型流感新靶点的新抑制化合物，用于开发新的单一和联合抗病毒药物疗法；这是一个指定的NIAID高度优先关注的领域。

DESCRIPTION (provided by applicant): The influenza A virus represents one of the greatest global human health risks. While 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 resistant as well as novel 2009 pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Amantadine- resistance has become so widespread the amantadanes have become all but ineffective and some flu strains have already exhibited significant resistance to neuraminidase inhibitors. 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. Thus, there is an urgent need for new and more effective antiviral mono- and combination therapies. Here we provide an innovative approach to identify inhibitors of both amantadine-sensitive and -resistant forms of the M2 proton channel to provide novel broad-spectrum therapeutics. Using this approach we provide a platform for the identification of new inhibitory compounds acting at novel sites of a clinically validated influenza A target for the development of new mono- and combination antiviral drug therapies; a designated NIAID high priority area of interest.