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。尼帕病毒（NiV）和亨德拉病毒（HeV）是副粘病毒科新定义的亨尼帕病毒属成员。尼帕病毒是一种突发副粘病毒，可在高达74%的感染患者中引起致命性脑炎，并且有越来越多的证据表明存在人际传播。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。特别是NiV，如果用于养猪业，可能会成为农业生物恐怖主义的破坏性代理人。内皮合胞是NiV感染的一个病理特征，由融合(F)和附着(G)包膜糖蛋白介导。我们最近发现ephrinB2是NiV和HeV的受体，内皮细胞和神经元上ephrinB2的表达在很大程度上解释了NiV和HeV的已知细胞趋向性。新冠病毒受体的鉴定为新冠病毒感染的病理生物学研究提供了线索，并可促进有效治疗方法的合理开发。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文库，并获得了候选的小分子拮抗剂，可以阻断NiV包膜与其同源受体的相互作用。为了响应RFA-AI-05-019（生物防御合作研究伙伴关系），我们提出了一项高度协作，跨学科，跨中心的研究工作，将协同Michael Jung博士（合作PI）的合成有机化学专业知识，Benhur Lee博士（PI）的病毒受体相互作用专业知识，以及Ramon Flick博士（Galveston UTMB的合作PI）的生物防御和BSL4病毒学专业知识，开发针对NiV的治疗方法。我们提出了以下具体目标，旨在鉴定一种先导化合物，该化合物可以开发成针对NiV的治疗药物，也可能是针对HeV。它们是：(1)开发阻断NiV和HeV进入的小分子拮抗剂；(2)在BSL4条件下的活病毒攻毒实验中评估这些小分子进入抑制剂的抗病毒效果。目标1利用UCLA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利用已经相当大的联邦投资在加尔维斯顿UTMB的BSL4设施。Ramon Flick博士是加尔维斯顿UTMB BSL4设施的联合主任，并且已经与PI合作进行了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，它们是致命的，可能是生物恐怖主义和农业恐怖主义（破坏畜牧业）的破坏性病原体。拟议的研究如果成功，将导致开发有效的抗尼帕病毒（和亨德拉病毒）疗法，可用于应对这些重点病原体的暴发。

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.