Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses

总结 流感病毒是全球范围内因呼吸道病毒感染而导致人类疾病的主要原因。是 这一伙伴关系的总体目标是推进一种新型嘧啶类似物抗流感病毒类 一个研究性的新药开发包。这个项目的设计是由我们的基础驱动的， 假设治疗流感的有效的下一代治疗剂必须是口服的， 对人、禽和猪谱系的流感病毒分离株显示出广泛的适应症谱，并且 包括甲型流感（IAV）和B（IBV）病毒。这些产品配置文件的要求来自临床 由于季节性流感病毒的多样性造成的负担， 人畜共患病病毒向人群的溢出，以及目前FDA的建议，承认非 患有季节性流感的住院成人作为初始临床检测的主要患者人群。 这些发展目标最好用直接作用的治疗剂来实现，因为靶向宿主的抗病毒药物 尽管这些疗法的适应症范围通常非常广泛，但它们易于产生不可接受的副作用， 与追求的主要患者群体不相容。 在学术界和业界长期的抗病毒合作关系下，我们建立了一个双重的 病原体药物筛选方案，允许同时自动识别靶病毒特异性 和广谱候选人。在大规模药物筛选活动中实施该测定， 产生具有亚微摩尔抗病毒效力的胞苷类似物。在支持该临床前研究的初步研究中， 程序，我们已经证明了有效的抑制活性延伸到IAV和IBV分离株，包括病毒 代表人类和人畜共患病谱系，包括高致病性禽H5N1和H7N9病毒， 大流行病的威胁。先导化合物是口服生物可利用的，有效地转化为活性物质， 三磷酸盐，并显示持续的微摩尔肺组织浓度。我们已经证明了口头 在小鼠中对具有大流行潜力的季节性和高致病性禽流感病毒的效力， 在豚鼠IAV传播模型中观察到病毒传播的实质性抑制。在制备 在临床试验中，将对该电极导线类别进行机械表征和电阻分析（目标1）。 与此同时，将探索磷脂前药制剂以提高重度抑郁症患者的药物组织浓度。 疾病适应症和我们筛选中确定的结构独立的替代方案将通过 化学先导开发作为后备，以减轻开发失败的潜在风险（目标2）。 将研究新兴磷脂前药和备用先导药物的药代动力学和药效学特征， 产生并测定体内耐受性（目的3）。临床候选药物对季节性和 将在小鼠和雪貂中测试高致病性病毒， 检查，并在豚鼠中评估对病毒传播的影响（目标4）。

Summary Influenza viruses are the leading cause of human disease due to respiratory viral infection worldwide. It is the overarching objective of this partnership to advance a novel pyrimidine analog anti-influenza virus class towards an investigational new drug-enabling package. The design of this program is driven by our underlying hypothesis that effective next-generation therapeutics for the treatment of influenza must be orally available, display a broad indication spectrum against influenza virus isolates of human, avian, and swine lineages, and covers both influenza A (IAV) and B (IBV) viruses. These product profile demands are derived from the clinical burden imposed by the diverse spectrum of seasonal influenza viruses, the pandemic potential arising from spillover of zoonotic viruses into the human population, and current FDA recommendations that recognize non- hospitalized adults suffering from seasonal influenza as the primary patient population for initial clinical testing. These developmental objectives are best met with direct acting therapeutics, since host-targeted antiviral therapies, although often tantalizingly broad in indication range, are prone to unacceptable side effects that are incompatible with the primary patient group pursued. Under the umbrella of a long-term academia/industry antiviral partnership, we have established a dual- pathogen drug screening protocol that allows the simultaneous automated identification of target virus-specific and broad-spectrum candidates. Implementation of this assay in a large-scale drug screening campaign has yielded a cytidine analog with sub-micromolar antiviral potency. In pilot studies underpinning this preclinical program, we have demonstrated that potent inhibitory activity extends to IAV and IBV isolates, covers viruses representing human and zoonotic lineages, and includes highly pathogenic avian H5N1 and H7N9 viruses of major pandemic threat. The lead compound is orally bioavailable, efficiently converted to the active triphosphate in vivo, and showed sustained micromolar lung tissue concentrations. We have demonstrated oral efficacy in mice against seasonal and highly pathogenic avian influenza viruses with pandemic potential and observed substantial suppression of viral spread in the guinea pig IAV transmission model. In preparation of clinical testing, this lead class will be subjected to mechanistic characterization and resistance profiling (aim 1). In parallel, phospholipid prodrug formulations will be explored to boost drug tissue concentrations for severe disease indications and a structurally independent alternative identified in our screen will be advanced through chemical lead development for back-up to alleviate the potential risk of developmental failure (aim 2). Pharmacokinetic and pharmacodynamic profiles of emerging phospholipid prodrug and back-up leads will be generated and in vivo tolerability determined (aim 3). Efficacy of clinical candidates against seasonal and highly-pathogenic viruses will be tested in mice and ferrets, the effect of prior drug exposure on pathogenesis examined, and the impact on viral spreads assessed in guinea pigs (aim 4).