Small molecule inhibitors of influenza virus nucleoprotein

流感是一个持续的全球公共卫生威胁，季节性活动没有得到充分控制 一年一度的疫苗计划。随着新流感的出现，这个问题的严重性可能会增加。 这种情况因新冠肺炎大流行而变得更加复杂。 新冠肺炎和2009年H1N1流感大流行都提醒人们，紧急情况下 它们还突出表明，如果出现更多的威胁，全球防备工作存在弱点。尽管 现有的季节性疫苗和目前使用的两类化学药物，都有迫切的需求 为新的抗流感治疗药物提供更广泛的覆盖范围，确保不出现药物 抵抗并为未来不可避免的大流行做好准备。这一阶段的STTR应用是为了开发强大的 一种新的病毒靶点核蛋白NP的抑制剂。我们已经确定并表征了两类抑制剂， 具有良好的亲和力和效价，无细胞毒性，具有良好的PK特性。第一阶段的目标是 在小鼠模型中展示体内疗效，在细胞培养中选择并鉴定逃逸突变体，以及 进一步探索我们的系列之一，有更多药物化学的极好机会。包括在此 努力是创造对H1N1和H3N2季节性病毒有效的广谱抗病毒药物的重要目标 菌株--鉴于NP靶标的高度保守性，这是可以实现的。我们的方法分为以下几种 三、整合具体目标。在目标1中，将使用BALB/c小鼠感染模型来研究 领导JJNP9-4和MC-2，基于成功的小鼠MTD和PK研究。将有几个参数 作为疗效指标衡量，包括死亡率、体重、肺部病毒载量和其他标准 行为和生理参数。在目标2中，JJNP9-4和MC-2将用于病毒逃逸的选择 突变，然后对突变进行测序，反向耐药变异体的基因结构，以及 逃逸突变体的病毒适合性特征。这些结果将为未来的结构研究提供信息，以确定 抑制剂的结合部位。在目标3中，一个缓蚀剂系列的效力将通过开发 合成单个类比和组合库的SAR将是两个最优先的类比 用于MTD、PK和小鼠感染模型的疗效研究。

Influenza is a continuing worldwide public health threat, with seasonal activity that is not adequately controlled by the yearly vaccine program. The severity of this problem is likely to increase with emergence of new influenza virus strains in the human population, and this situation is made even more complex by the COVID-19 pandemic. Both COVID-19 and the 2009 H1N1 influenza pandemics are reminders of the challenge posed by emergent viruses, and they also highlight weaknesses in global preparedness should additional threats arise. Despite existing seasonal vaccines and two classes of chemical pharmaceuticals in current use, there is an urgent need for new anti-influenza therapeutic agents to provide broader coverage, ensure against emergence of drug resistance and prepare for future inevitable pandemics. This Phase I STTR application is to develop potent inhibitors to a novel viral target, the nucleoprotein NP. We have identified and characterized two inhibitor classes, with promising affinity and potency, lack of cytotoxicity and good PK properties. The goals of Phase I are to demonstrate in vivo efficacy in the mouse model, select and characterize escape mutants in cell culture, and further explore one of our series with excellent opportunities for additional medicinal chemistry. Included in this effort is the important goal of creating broad-spectrum antivirals that are active against H1N1 and H3N2 seasonal strains – which is achievable given the highly conserved nature of the NP target. Our approach is divided among three, integrated Specific Aims. In Aim 1 the BALB/c mouse infection model will be used for efficacy studies of leads JJNP9-4 and MC-2, based on successful MTD and PK studies in the mouse. Several parameters will be measured as indicators of efficacy, including mortality, body weight, viral load in the lung and other standard behavioral and physical parameters. In Aim 2, JJNP9-4 and MC-2 will be used for selection of virus escape mutants, followed by sequencing of the mutants, reverse genetic construction of drug-resistant variants, and characterization of viral fitness of the escape mutants. The results will inform future structural studies to identify the binding sites of the inhibitors. In Aim 3 the potency of one inhibitor series will be addressed by developing an SAR with the synthesis of individual analogs and combinatorial libraries Two top-prioritized analogs will be used for MTD, PK and efficacy studies in the mouse model of infection.