OPTIMIZATION OF NOVEL INFLUENZA M2 CHANNEL INHIBITORS

描述(申请人提供)：甲型流感病毒是一个主要的全球卫生问题。尽管美国每年都有疫苗接种计划，但每年仍有10%-15%的人口受到感染，估计有3.6万人死亡，20万人住院。两类抗病毒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年甲型H1N1流感大流行和高致病性(H5N1)新型甲型流感病毒株。在一些甲型流感病毒株中也观察到对神经氨酸酶抑制剂的显著耐药性。因此，迫切需要新的、更有效的抗病毒疗法。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，并抑制抗药性的出现。在这里，我们建议优化已鉴定的新型HIT系列化合物的效力和细胞毒性特性，这些化合物克服了当前的耐药机制，抑制了金刚烷胺敏感和耐药形式的M2质子通道。优化这些化学系列可以为甲型流感的单一和联合抗病毒药物的新疗法提供新的广谱疗法；这是NIAID指定的高度优先关注的领域。

DESCRIPTION (provided by applicant): Influenza A viruses are a major global health concern. Despite annual vaccination programs in the US, 10-15% of the population is infected annually accounting for an estimated 36,000 deaths and 200,000 hospitalizations. Two classes of antiviral 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 adamantanes have become all but ineffective. Significant resistance to neuraminidase inhibitors has also been observed in some influenza A strains. Thus, there is an urgent need for new and more effective antiviral therapies. 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 drug-resistance. Here we propose to optimize potency and cytotoxicity properties of identified novel hit series compounds that overcome current drug-resistance mechanisms to inhibit both amantadine-sensitive and -resistant forms of the M2 proton channel. Optimization of these chemical series could provide novel broad-spectrum therapeutics for new mono- and combination antiviral drug therapies for influenza A; a designated NIAID high priority area of interest.