DEVELOPMENT, VALIDATION, AND OPTIMIZATION OF HTS SCREENS TARGETING NIPAH AND HENDRA VIRUS RNA SYNTHESIS

针对尼帕病毒和亨德拉病毒 RNA 合成的 HTS 筛选的开发、验证和优化

• 批准号: 9470967
• 负责人: Gaya K. Amarasinghe
• 金额: $ 53.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470967
• 关键词: Address; Agriculture; Antiviral Agents; Australia; Bangladesh; Biochemical; Biochemistry; Biological; Biological Assay; Biological Products; Bioterrorism; Canis familiaris; Case Fatality Rates; Categories; Cells; Chemicals; Chiroptera; Clinical; Complex; Containment; Coupled; Development; Disease Outbreaks; Ebola virus; Emerging Communicable Diseases; Encephalitis; Equus caballus; Exhibits; Family; Family suidae; Felis catus; Fluorescence Polarization; Future; Genetic Transcription; Genus Pteropus; Glycine decarboxylase; Goals; Hendra Virus; Henipavirus; Human; In Vitro; India; Infection prevention; Lead; Livestock; Malaysia; Molecular; NP protein; National Institute of Allergy and Infectious Disease; Nipah Virus; Paramyxoviridae; Paramyxovirus; Pathogenicity; Pharmaceutical Preparations; Population; Public Health; RNA Viruses; RNA chemical synthesis; RNA-Directed RNA Polymerase; Reproducibility; Research; Sensitivity and Specificity; Site; Therapeutic; Universities; Vaccines; Validation; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Washington; Zoonoses; assay development; base; drug development; drug discovery; efficacy testing; experience; global health; health economics; high throughput screening; inhibitor/antagonist; innovation; insight; medical schools; member; pathogen; protein protein interaction; response; screening; structural biology; therapeutic target; transmission process; viral RNA

Nipah virus (NiV) and Hendra virus (HeV) are related highly pathogenic zoonotic henipaviruses in the paramyxovirus family that use bats from the Pteropus genus as reservoir hosts. NiV exhibits an unusually broad host range for a paramyxovirus and infects pigs, dogs, and cats. Although first identified in an outbreak in Malaysia, near annual outbreaks in Bangladesh and India are now known to occur with average case fatality rates of 73%. HeV infections have occurred in Australia where infected horses transmitted the virus to seven humans of whom four died. Both NiV and HeV have also caused late-onset lethal encephalitis in humans. Because of their high lethality in humans, the absence of approved vaccines or treatments, and evidence of NiV human to human transmission, these viruses are NIAID Emerging Infectious Diseases/Pathogens Category C Priority Pathogens. In addition, henipaviruses can infect livestock and are serious threats to agriculture. Despite the potential for severe public health and economic consequences, research into these viruses has lagged, reflecting in part the need for biosafety level 4 containment to study replicating virus. Importantly, there are no drugs currently available to treat or prevent these infections. Recent studies have started to provide insight into the determinants of viral pathogenesis and to define at the atomic and molecular levels how transcription and replication activities are carried out by the viral RNA-dependent RNA polymerase complex (also known as the viral RDRP complex). The viral RDRP complex has obvious potential as a therapeutic target, but sensitive reliable screens and secondary assays are needed to identify and validate inhibitors of this complex. Our recent collaborative studies defined an analogous interaction between Ebola VP35 and NP proteins that is currently being developed as a therapeutic target. In order to address a major unmed need for NiV and HeV therapeutics, we will use this successful framework to develop in vitro and cell-based assays that target the interface between NiV and HeV N and P proteins. We expect to identify replication inhibitor leads targeting zoonotic henipaviruses that will facilitate biological probe and antiviral development.

尼帕病毒（Nipah virus，NiV）和亨德拉病毒（Hendra virus，HeV）是两种高度致病的人畜共患亨德拉病毒 属于副粘病毒科，以狐蝠属的蝙蝠为宿主。和合 副粘病毒表现出异常广泛的宿主范围，并感染猪、狗和猫。 虽然首次在马来西亚的一次疫情中发现，但孟加拉国和 印度现在已知发生的平均病死率为73%。HeV感染 在澳大利亚发生了一起感染的马将病毒传染给了七个人， 死了NiV和HeV也都在人类中引起迟发性致命脑炎。因为 它们在人类中的高致命性，缺乏批准的疫苗或治疗方法，以及 NiV人传人，这些病毒是NIAID新兴传染病 疾病/病原体C类优先病原体此外，亨尼帕病毒可以感染 畜牧业是对农业的严重威胁。尽管有可能对公众健康造成严重影响 和经济后果，对这些病毒的研究已经滞后，部分反映了需要 进行生物安全4级控制，以研究复制病毒。重要的是，没有药物 目前可用于治疗或预防这些感染。最近的研究已经开始提供 深入了解病毒发病机制的决定因素，并在原子和分子水平上定义 水平如何转录和复制活动进行的病毒RNA依赖 RNA聚合酶复合物（也称为病毒RDRP复合物）。病毒RDRP复合物 作为治疗靶点具有明显的潜力，但敏感可靠的筛选和次要的 需要测定来鉴定和验证该复合物的抑制剂。我们最近的合作 研究确定了埃博拉病毒VP 35和NP蛋白之间的类似相互作用， 被开发为治疗靶点。为了解决一个主要的非医疗需要NiV和 HeV疗法，我们将利用这一成功的框架， 靶向NiV和HeV N和P蛋白之间界面的测定。我们希望能找出 靶向人畜共患亨尼帕病毒的复制抑制剂先导物， 抗病毒的发展。