Small Molecule Inhibitors of Nipah and Hendra Virus Infection

描述（由申请人提供）： 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（NiV）和亨德拉（HeV）病毒是副粘病毒科的新定义的亨帕病毒属的成员。尼帕病毒（NiV）是一种新出现的副粘病毒，在高达74%的感染患者中引起致命性脑炎，并且越来越多的证据表明人传人。NiV和HeV在NIAID生物防御研究议程中被指定为BSL 4和优先病原体。特别是NiV，如果用于养猪业，可能是农业生物恐怖主义的破坏性因子。内皮合胞体是NiV感染的特征性特征，并且由融合（F）和附着（G）包膜糖蛋白介导。我们最近确定ephrinB 2作为NiV和HeV受体，并且ephrinB 2在内皮细胞和神经元上的表达在很大程度上解释了NiV和HeV的已知细胞向性。NiV受体的鉴定揭示了NiV感染的病理生物学，并且可以刺激有效治疗方法的合理开发。特别是，我们已经使用我们的知识NiV受体相互作用和分子筛选共享资源在加州大学洛杉矶分校筛选小分子化学库，并获得了候选的小分子拮抗剂，阻断NiV包膜与其同源受体的相互作用。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合作，跨学科和跨中心的研究工作，将协同迈克尔荣格博士（合作PI）的合成有机化学专业知识，本胡尔李博士（PI）的病毒-受体相互作用专业知识，以及Ramon Flick博士（UTMB，加尔维斯顿的共同Pi）的生物防御和BSL 4病毒学专业知识，以开发针对NiV的治疗方法。我们提出了以下具体目标，这些目标旨在鉴定可以开发成针对NiV和可能的HeV的治疗剂的先导化合物。它们是：（1）开发阻断NiV和HeV进入的小分子拮抗剂，和（2）在BSL 4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功效。目标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NiV的进入抑制剂，目标2利用加尔维斯顿UTMB的BSL 4设施中已经相当大的联邦投资。Ramon Flick博士是加尔维斯顿UTMB的BSL 4设施的联合主任，并且已经与PI合作进行NiV进入实验。公共卫生相关性：尼帕病毒和亨德拉病毒被指定为优先病原体，是致命的，并且可以是生物恐怖主义和农业恐怖主义的破坏性因子（对畜牧业的破坏）。拟议的研究如果成功，将导致开发有效的抗尼帕（和亨德拉）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.