Discovery of novel Henipavirus inhibitors

新型亨尼帕病毒抑制剂的发现

• 批准号: 10514154
• 负责人: Thomas William Geisbert
• 金额: $ 529.18万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514154
• 关键词: 2019-nCoV; African Green Monkey; Animals; Antiviral Agents; Antiviral Therapy; Automation; Bangladesh; Biochemical; Biological Assay; Biology; Case Fatality Rates; Cells; Chemicals; Communicable Diseases; Containment; Coronavirus; Country; Crystallization; Dengue; Dengue Virus; Development; Disease; Disease Outbreaks; Drug Design; Drug Targeting; Drug resistance; Encephalitis; Evaluation; Family; Flavivirus; Generations; Goals; Hamsters; Hendra Virus; Henipavirus; Human; In Vitro; India; Infection; Lead; Luciferases; Malaysia; Maps; Medical; Miniaturization; Modeling; Modernization; Mutation; Nipah Virus; Paramyxovirus; Pathogenicity; Persons; Pharmaceutical Chemistry; Phase I/II Clinical Trial; Phenotype; Philippines; Proteins; Recombinants; Research; Rodent; Services; Structure; Structure-Activity Relationship; System; Technology; Testing; Texas; Therapeutic; Triage; Universities; Vaccines; Variant; Viral; Viral Genes; Virus; animal efficacy; base; biophysical techniques; biosafety level 4 facility; clinical candidate; combat; cytotoxicity; drug discovery; drug resistant virus; efficacy study; high throughput screening; human pathogen; in vivo; in vivo Model; inhibitor; lead optimization; man; member; novel; pandemic disease; pandemic preparedness; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; protective efficacy; respiratory; respiratory pathogen; reverse genetics; safety study; screening; small molecule; tool; transmission process; virology; whole genome

PROJECT 3 – ABSTRACT The goal of this project is to discover novel henipavirus inhibitors. Henipavirus is a deadly airborne respiratory pathogen that are under-researched and poorly understood. Antiviral therapy is urgently needed for henipaviruses for pandemic preparedness. We will achieve the goal by pursuing three aims. (i) Screen and identify novel compounds for Nipah and/or Hendra virus inhibition. Since Nipah and Hendra viruses should be handled at BSL4, it is challenging to perform high-throughput screen at high containment. To overcome this bottleneck, we will use a BSL2 Cedar henipavirus as a surrogate system for antiviral screen. Hits identified from the Cedar henipavirus assay will be validated in Hendra and Nipah viruses at the BSL4 facility. (ii) Develop tool compounds, determine target protein, and optimize molecules. (iii) Evaluate lead compounds in relevant in vitro and in vivo models and select Development Candidate for IND-enabling studies. The proposed cell-based approach may discover novel antiviral targets that may not be tractable for target-based antiviral approach.

项目 3 – 摘要 该项目的目标是发现新型亨尼帕病毒抑制剂。亨尼帕病毒是一种致命的空气传播呼吸道病毒 病原体尚未得到充分研究和了解。迫切需要抗病毒治疗 用于大流行防范的亨尼帕病毒。我们将通过追求三个目标来实现这一目标。 (i) 屏幕和 鉴定用于抑制尼帕病毒和/或亨德拉病毒的新化合物。由于尼帕病毒和亨德拉病毒应该是 在 BSL4 进行处理，在高封闭性下进行高通量筛选具有挑战性。为了克服这个 瓶颈，我们将使用 BSL2 Cedar henipavirus 作为抗病毒筛选的替代系统。识别出的命中 Cedar 亨尼帕病毒检测将在 BSL4 设施的亨德拉病毒和尼帕病毒中进行验证。 (二) 开发工具 化合物、确定目标蛋白质并优化分子。 (iii) 评估相关体外先导化合物 和体内模型，并选择用于 IND 研究的开发候选者。所提出的基于细胞的 方法可能会发现新的抗病毒靶点，而基于靶点的抗病毒方法可能无法处理这些靶点。