Development of novel broad-spectrum influenza A inhibitors

描述（由申请人提供）：甲型流感病毒是全球最大的人类健康风险之一。虽然疫苗对季节性流感感染提供了重要的保护，但仅在美国，每年仍有36000人死亡，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。已有两类药物被批准用于预防和治疗流感。令人震惊的是，在过去十年中出现了耐药性以及2009年新型大流行甲型流感（H1N1）和高致病性甲型流感（H5N1）毒株。金刚烷胺耐药性已经变得如此普遍，以至于金刚烷胺几乎失效，一些流感毒株已经表现出对神经氨酸酶抑制剂的显著耐药性。正如治疗其他病毒性疾病所采用的那样，最理想的做法是使用联合药物疗法，以提供最有效的预防和治疗，并抑制其他耐药性的出现。因此，迫切需要新的和更有效的抗病毒单一和联合治疗。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，以提供新的广谱治疗方法。利用这种方法，我们为鉴定在临床验证的甲型流感靶点的新位点起作用的新抑制化合物提供了一个平台，用于开发新的单一和联合抗病毒药物治疗；指定的NIAID高优先级领域。

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. PUBLIC HEALTH RELEVANCE: Over the past decade the emergence of a number of drug-resistant and/or highly pathogenic variants of influenza have dramatically increased the potential impact of influenza infection. This proposal details an innovative approach to identify much needed novel inhibitors and potential therapeutics for the prevention and treatment of influenza A infection for mono and combination drug therapies.