Small molecule inhibitors of influenza virus nucleoprotein

流感病毒核蛋白小分子抑制剂

• 批准号: 10255568
• 负责人: DANIEL A ENGEL
• 金额: $ 30万
• 依托单位: ALEXANDER BIODISCOVERIES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255568
• 关键词: Address; Affect; Affinity; Antiviral Agents; Behavioral; Binding Sites; Body Weight; COVID-19; COVID-19 pandemic; Cell Culture Techniques; Cessation of life; Chemicals; Complex; Drug resistance; Ensure; Escape Mutant; Future; Goals; Hospitalization; Human; In Vitro; Inbred BALB C Mice; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Libraries; Lung; Measures; Mind; Modeling; Mus; Nature; Nucleoproteins; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Population; Property; Public Health; Readiness; Research; Series; Severities; Small Business Technology Transfer Research; Solubility; Structure; Therapeutic Agents; Toxic effect; United States; Vaccines; Variant; Viral; Viral Load result; Virus; analog; anti-influenza; aqueous; base; combat; combinatorial; cytotoxicity; efficacy study; improved; in vivo; influenza epidemic; influenza virus strain; influenzavirus; inhibitor/antagonist; mortality; mouse model; mutant; novel; novel therapeutics; pandemic disease; pandemic influenza; programs; reverse genetics; small molecule inhibitor; viral fitness

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.

流感是一种持续的全球性公共卫生威胁，其季节性活动未得到充分控制 每年的疫苗接种计划。随着新型流感的出现，这一问题的严重性可能会增加 病毒株在人群中传播，而COVID-19大流行使这种情况变得更加复杂。 COVID-19和2009年H1N1流感大流行都提醒人们， 它们还突出表明，如果出现新的威胁，全球防范工作存在薄弱环节。尽管 现有的季节性疫苗和目前使用的两类化学药品， 为新的抗流感治疗药物提供更广泛的覆盖面，确保防止药物的出现 并为未来不可避免的流行病做好准备。第一阶段STTR应用程序是开发有效的 抑制剂的一种新的病毒目标，核蛋白NP。我们已经鉴定并表征了两类抑制剂， 具有有希望的亲和力和效力、缺乏细胞毒性和良好的PK性质。第一阶段的目标是 在小鼠模型中证明体内疗效，在细胞培养物中选择和表征逃逸突变体，以及 进一步探索我们的系列之一，为其他药物化学提供绝佳的机会。纳入本 这一努力的重要目标是创造广谱抗病毒药物，对H1N1和H3 N2季节性 菌株-鉴于NP靶标的高度保守性质，这是可实现的。我们的方法分为 三是综合具体目标。在目的1中，BALB/c小鼠感染模型将用于以下的功效研究： 基于在小鼠中成功的MTD和PK研究，导致JJNP 9 -4和MC-2。几个参数将 作为疗效指标进行测量，包括死亡率、体重、肺中病毒载量等标准 行为和身体参数。在目的2中，JJNP 9 -4和MC-2将用于选择病毒逃逸 突变体，然后对突变体进行测序，逆转耐药变体的遗传构建，以及 逃逸突变体的病毒适应性的表征。研究结果将为未来的结构研究提供信息， 抑制剂的结合位点。在目标3中，一个抑制剂系列的效力将通过开发 合成单个类似物和组合文库的SAR。 用于小鼠感染模型中的MTD、PK和功效研究。