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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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:
    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:
    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:
    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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