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

摘要 流感病毒是世界范围内呼吸道病毒感染导致人类疾病的主要原因。它是 这一合作伙伴关系的首要目标是开发一种新型的嘧啶类似物抗流感病毒 朝向一项研究新药的一揽子计划。这个程序的设计是由我们的底层驱动的 假设治疗流感的有效的下一代疗法必须是口服的， 展示针对人类、禽类和猪系流感病毒分离株的广泛指示范围，以及 涵盖甲型流感病毒(IAV)和乙型流感病毒(IBV)。这些产品配置文件需求源自临床 季节性流感病毒的多样性造成的负担，大流行的潜在原因是 人畜共患病病毒对人类的溢出效应，以及FDA目前的建议，承认非 以患有季节性流感的住院成人为主要患者人群进行初步临床检测。 直接作用疗法最能满足这些发育目标，因为宿主靶向的抗病毒药物 尽管治疗的适应症范围往往非常广泛，但容易产生不可接受的副作用，这些副作用 与所追求的主要患者组不相容。 在学术界和业界的长期抗病毒伙伴关系下，我们建立了一个双重的- 病原体药物筛选协议，允许同时自动识别目标病毒特异性 和广谱的候选人。在一次大规模的药物筛选活动中实施了这种检测方法 产生了一种具有亚微摩尔抗病毒效力的胞苷类似物。在支持这一临床前研究的先导研究中 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，覆盖病毒 代表人类和人畜共患病谱系，包括高致病性禽流感H5N1和H7N9病毒 重大流行病威胁。先导化合物是口服生物利用型的，有效地转化为活性物质。 三磷酸盐在体内，并显示出持续的微摩尔肺组织浓度。我们已经演示了口述 小鼠对季节性和高致病性禽流感病毒的疗效 在豚鼠IAV传播模型中观察到病毒传播受到实质性抑制。在准备过程中 在临床测试中，这一先导类别将接受机械性表征和耐药性分析(目标1)。 同时，将探索磷脂前体药物配方，以提高重症患者的药物组织浓度 在我们的屏幕上确定的疾病适应症和结构独立的替代方案将通过 发展化学铅作为后备，以减轻发育障碍的潜在风险(目标2)。 新出现的磷脂前药和后备药物的药代动力学和药效学概况将如下 产生和体内耐受性确定(目标3)。临床候选人对季节性和非季节性疾病的疗效 高致病性病毒将在小鼠和雪貂身上进行测试，先前接触药物对发病机制的影响 进行了检查，并评估了对病毒在豚鼠中传播的影响(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).