Small Molecule Inhibitors of Nipah and Hendra Virus Infection

描述(申请人提供)：新出现的病毒病原体对美国的健康和经济构成严重威胁。尼帕(Nipah，NIV)和亨德拉(Hendra，HEV)病毒是副粘病毒科新定义的海尼帕病毒属成员。尼帕病毒(Nipah Virus，NIV)是一种紧急副粘病毒，可导致高达74%的感染患者发生致命性脑炎，越来越多的证据表明它在人与人之间传播。NIV和HEV在NIAID生物防御研究议程中被指定为BSL4和优先病原体。尤其是，如果用来对付养猪业，可能是农业生物恐怖主义的毁灭性因素。内皮合胞体是新城疫病毒感染的一种病原学特征，由融合(F)和附着(G)包膜糖蛋白介导。最近，我们发现ewitinB2是NIV和HEV的受体，在血管内皮细胞和神经元上的表达很大程度上解释了已知的NIV和HEV的细胞趋向性。新城疫病毒受体的鉴定有助于阐明新城疫病毒感染的病理生物学机制，并可促进有效治疗药物的合理开发。特别是，我们利用我们对NIV-受体相互作用的知识和加州大学洛杉矶分校的分子筛选共享资源来筛选小分子化学库，并获得了阻断NIV包膜与其同源受体相互作用的候选小分子拮抗剂。为了响应RFA-AI-05-019(生物防御合作研究伙伴关系)，我们提出了一个高度协作、跨学科和跨中心的研究工作，将结合Michael Jung博士(共同PI)的合成有机化学专业知识、Benhur Lee博士(PI)的病毒与受体相互作用的专业知识以及Ramon Flick博士(UTMB，加尔维斯顿联合PI)的生物防御和BSL4病毒学专业知识，开发一种针对新城疫的治疗方法。我们提出了以下具体目标，旨在鉴定一种可以开发成治疗新城疫和可能的戊型肝炎病毒的先导化合物。它们是：(1)开发阻断NIV和HEV进入的小分子拮抗剂，以及(2)在BSL4条件下的活病毒攻击实验中评估这些小分子进入抑制剂的抗病毒效果。AIM 1利用加州大学洛杉矶分校现有的基础设施和跨学科专业知识来识别和优化新城疫的进入抑制剂，而AIM 2利用联邦政府对加尔维斯顿UTMB的BSL4设施已经相当大的投资。Ramon Flick博士是加尔维斯顿UTMB BSL4设施的联席主任，并已与PI合作进行Niv进入实验。公共卫生相关性：Nipah和Hendra病毒被指定为优先病原体，是致命的，可能是生物恐怖主义和农业恐怖主义的破坏性因素(对活畜业的破坏)。拟议的研究如果成功，将导致开发有效的抗Nipah(和Hendra)疗法，可用于应对这些优先病原体的爆发。

DESCRIPTION (provided by applicant): Emerging viral pathogens present a critical threat to U.S. health and economy. Nipah (NiV) and Hendra (HeV) viruses are members of the newly defined Henipavirus genus of the Paramyxoviridae. Nipah virus (NiV) is an emergent paramyxovirus that causes fatal encephalitis in up to 74% of infected patients, and there is increasing evidence of human-to-human transmission. NiV and HeV are designated as BSL4 and priority pathogens in the NIAID Biodefense Research Agenda. NiV, in particular, could be a devastating agent of agrobioterrorism if used against the pig farming industry. Endothelial syncytia are a pathognomonic feature of NiV infections, and are mediated by the fusion (F) and attachment (G) envelope glycoproteins. We recently identified ephrinB2 as the NiV and HeV receptor, and the expression of ephrinb2 on endothelial cells and neurons largely explains the known cellular tropism of both NiV amd HeV. The identification of the NiV receptor has shed light on the pathobiology of NiV infection, and can spur the rational development of effective therapeutics. In particular, we have used our knowledge of NiV-receptor interactions and the Molecular Screening Shared Resource at UCLA to screen small molecule chemical libraries, and have obtained candidate small molecule antagonists that block NiV envelope interactions with its cognate receptor. In response to RFA-AI-05-019 (Co-operative Research Partnership for Biodefense), we have proposed a highly collaborative, inter-disciplinary, and trans-center research effort that will synergize the synthetic organic chemistry expertise of Dr. Michael Jung (co-PI), the virus-receptor interaction expertise of the Dr. Benhur Lee (PI), and the biodefense and BSL4 virological expertise of Dr. Ramon Flick (co-Pi at UTMB, Galveston), to develop a therapeutic against NiV. We propose the following Specific Aims that are geared towards the identification of a lead compound that can be developed into a therapeutic against NiV, and likely, HeV. They are: (1) To develop small molecule antagonists that block NiV and HeV entry, and (2) To assess the anti-viral efficacy of these small molecule entry inhibitors in live virus challenge experiments under BSL4 conditions. Aim 1 exploits the infrastructure and inter-disciplinary expertise already present at UCLA to identify and optimize entry inhibitors of NiV, and Aim 2 makes use of the already sizable federal investment in the BSL4 facilities at UTMB, Galveston. Dr. Ramon Flick is the co-director of the BSL4 facility at UTMB, Galveston, and has already collaborated with the PI on NiV entry experiments. Public Health Relevance: Nipah and Hendra viruses are designated priority pathogens, are deadly, and can be devastating agents of bioterrorism and agroterrorism (devastation of the live-stock industry). The proposed studies, if successful, will lead to the development of effective anti-Nipah (and Hendra) therapeutics that can be used in response to an outbreak of these priority pathogens.