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

针对季节性和高致病性流感病毒的广谱抑制剂的开发

基本信息

  • 批准号:
    10080034
  • 负责人:
  • 金额:
    $ 97.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-08 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

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).
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, 产生了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试点研究中 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)。

项目成果

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Richard K. Plemper其他文献

Cryo-Electron Tomography Provides Insight into the Native Architecture of the Measles Virus Assembly Site
冷冻电子断层扫描可深入了解麻疹病毒装配位点的原生结构
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    J. Strauss;Ke Zunlong;Richard K. Plemper;E. Wright
  • 通讯作者:
    E. Wright
The Near-to-Native-State Architecture of Measles Virus Assembly Sites and Isolated Measles Virus Particles
麻疹病毒组装位点和分离的麻疹病毒颗粒的接近天然状态的结构
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    E. Wright;J. Strauss;Ke Zunlong;Cheri M. Hampton;Fredrick Leon;M. Brindley;Richard K. Plemper
  • 通讯作者:
    Richard K. Plemper
Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity
ERDRP-0519 治疗麻疹病毒聚合酶可抑制所有 RNA 合成活性
  • DOI:
    10.1101/2020.09.23.311043
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    R. Cox;Julien Sourimant;M. Govindarajan;M. Natchus;Richard K. Plemper
  • 通讯作者:
    Richard K. Plemper
Capturing Enveloped Viruses on Affinity Grids for Downstream Cryo-Electron Tomography Applications
在亲和网格上捕获包膜病毒以用于下游冷冻电子断层扫描应用
  • DOI:
    10.1017/s1431927613002274
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    Gabriella Kiss;Xuemin Chen;J. Holl;M. Brindley;P. Campbell;A. Lauren;Byrd;J. Steel;D. Steinhauer;C. Afonso;Richard K. Plemper;Paul;Spearman;Deborah F. Kelly;E. Wright
  • 通讯作者:
    E. Wright
121 INTESTINAL MICROBIOME INFLUENCES SEVERITY OF RESPIRATORY VIRAL INFECTION VIA IMPACTING ALVEOLAR MACROPHAGES
  • DOI:
    10.1016/s0016-5085(23)01001-6
  • 发表时间:
    2023-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Vu L. Ngo;Carolin M. Lieber;Richard K. Plemper;Andrew T. Gewirtz
  • 通讯作者:
    Andrew T. Gewirtz

Richard K. Plemper的其他文献

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{{ truncateString('Richard K. Plemper', 18)}}的其他基金

Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors
项目 1 — 口服生物可利用的 β-CoV 抑制剂的开发
  • 批准号:
    10513942
  • 财政年份:
    2022
  • 资助金额:
    $ 97.96万
  • 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
  • 批准号:
    10666509
  • 财政年份:
    2020
  • 资助金额:
    $ 97.96万
  • 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
  • 批准号:
    10425285
  • 财政年份:
    2020
  • 资助金额:
    $ 97.96万
  • 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
  • 批准号:
    10034283
  • 财政年份:
    2020
  • 资助金额:
    $ 97.96万
  • 项目类别:
Polymerase Inhibitors of Respiratory Syncytial Virus
呼吸道合胞病毒聚合酶抑制剂
  • 批准号:
    10199980
  • 财政年份:
    2020
  • 资助金额:
    $ 97.96万
  • 项目类别:
Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses
针对季节性和高致病性流感病毒的广谱抑制剂的开发
  • 批准号:
    10544324
  • 财政年份:
    2019
  • 资助金额:
    $ 97.96万
  • 项目类别:
Drug discovery against lyssaviruses by high thoughput screening
通过高通量筛选发现抗狂犬病病毒药物
  • 批准号:
    9218526
  • 财政年份:
    2016
  • 资助金额:
    $ 97.96万
  • 项目类别:
Identification and Hit-to-Lead Development of Influenza A Virus Inhibitors
甲型流感病毒抑制剂的鉴定和先导化合物开发
  • 批准号:
    8955538
  • 财政年份:
    2015
  • 资助金额:
    $ 97.96万
  • 项目类别:
Novel Therapeutics against Respiratory Syncytial Virus Infection
对抗呼吸道合胞病毒感染的新疗法
  • 批准号:
    8662435
  • 财政年份:
    2014
  • 资助金额:
    $ 97.96万
  • 项目类别:
Host-Directed Inhibitors of Myxovirus Replication
粘病毒复制的宿主定向抑制剂
  • 批准号:
    8566072
  • 财政年份:
    2012
  • 资助金额:
    $ 97.96万
  • 项目类别:

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