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

尼帕病毒(Nipah Virus，NIV)和亨德拉病毒(Hendra Virus，HEV)是相关的高致病性人畜共患埃尼帕病毒 在副粘病毒家族中，使用翼蝙蝠属的蝙蝠作为宿主。[和合] 副粘病毒的宿主范围异常广泛，并感染猪、狗和猫。 虽然最早是在马来西亚的一次疫情中发现的，但几乎每年都会在孟加拉国和 众所周知，印度目前的平均病死率为73%。戊型肝炎病毒感染已经 发生在澳大利亚，受感染的马将病毒传播给了七个人，其中四个人 死了。新城疫和戊型肝炎病毒也都导致了人类迟发性的致命性脑炎。因为. 它们对人类的高致命性，缺乏经批准的疫苗或治疗方法，以及 人与人之间的传播，这些病毒是NIAID新出现的传染病 疾病/病原体C类优先病原体。此外，埃尼帕病毒还可以感染 并对农业构成严重威胁。尽管有可能造成严重的公共卫生 和经济后果，对这些病毒的研究一直滞后，部分反映了需要 用于生物安全4级安全壳研究病毒复制。重要的是，没有毒品 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 洞察病毒致病的决定因素并从原子和分子上进行定义 转录和复制活动是如何由依赖于RNA的病毒进行的 RNA聚合酶复合体(也称为病毒RDRP复合体)。病毒RDRP复合体 具有作为治疗靶点的明显潜力，但敏感可靠的筛查和继发性 需要通过检测来鉴定和验证该复合体的抑制剂。我们最近的协作 研究确定了埃博拉VP35和NP蛋白之间的类似相互作用，目前 正被开发为治疗靶点。为了满足对NIV和NIV的重大需求 HEV治疗学，我们将利用这一成功的框架在体外和细胞基础上开发 针对新城疫病毒和戊型肝炎病毒N和P蛋白之间的界面的检测。我们希望能确定 复制抑制物领先于人畜共患埃博拉病毒，将促进生物探针和 抗病毒研发。

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.