GPCR antagonists as anti-Ebola virus entry inhibitors

 描述(申请人提供)：埃博拉(EBOV)和马尔堡(MARV)病毒属于丝状病毒科，可引起致命的出血热，特征是广泛的组织破坏，潜伏期为4-14天。出于安全考虑，这些病毒被指定为生物安全4级制剂。目前还没有针对人类丝状病毒感染和发病机制的有效疫苗或治疗方法。目前在西非持续的2014年埃博拉疫情已导致5000多人死亡，突显了治疗和控制这种致命病毒的全球挑战。这项申请定义了一个确定和开发有效的小分子抑制剂的计划，这些小分子抑制剂可以阻止EBOV进入宿主细胞。我们已经开发了一种针对埃博拉病毒进入的基于细胞的HTS方案，以识别阻止传染性埃博拉病毒进入的小分子抑制剂。这一第一阶段应用的总体目标是确定和开发这些抑制剂作为潜在的抗埃博拉疗法。此应用程序将重点关注以下三个具体目标：(1)确定有效 来自GPCR拮抗剂的小分子库中的抗埃博拉抑制剂，根据结构-活性关系(SARS)对最有效的抑制剂进行优先排序和化学修饰，以提高效力和选择性。(2)验证感染性化验中的铅抑制物候选 并对EBOV抑制剂的作用机制进行了研究。(3)筛选适合静脉注射的体外ADME性质的EBOV抑制剂。和口服剂量。

 DESCRIPTION (provided by applicant): Ebola (EBOV) and Marburg (MARV) viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of 4-14 days. Because of the safety concerns, these viruses are designated as biosafety level 4 agents. Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans. The current ongoing 2014 Ebola epidemic in West Africa has led to more than 5,000 deaths and underscores the global challenge of treating and controlling this deadly virus. This application defines a plan to identify and develop potent small molecule inhibitors, which block entry of EBOV into host cells. We have developed a cell-based HTS protocol targeting Ebola entry to identify small molecule inhibitors that block entry of infectious EBOV. The overall objective of this Phase I application is to identify and develop these inhibitors as potential anti-Ebola therapeutics. This application will focus on the following three specific aims: (1) Identify potent anti-Ebola inhibitors from a small molecule library of GPCR antagonists, prioritize and chemically modify the most potent inhibitors based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the EBOV inhibitors. (3) Select EBOV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.