GPCR antagonists as anti-Ebola virus entry inhibitors

 描述（由申请方提供）：埃博拉病毒（EBOV）和马尔堡病毒（MARV）属于丝状病毒科，可引起致命性出血热，其特征为广泛的组织破坏，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，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性治疗。2014年西非埃博拉疫情目前仍在持续，已导致5,000多人死亡，凸显了治疗和控制这一致命病毒的全球挑战。本申请定义了鉴定和开发有效的小分子抑制剂的计划，其阻断EBOV进入宿主细胞。我们已经开发了一种基于细胞的HTS方案，靶向埃博拉病毒进入，以鉴定阻断传染性EBOV进入的小分子抑制剂。该I期申请的总体目标是鉴定和开发这些抑制剂作为潜在的抗埃博拉治疗剂。本申请将集中在以下三个具体目标：（1）确定有效的 从GPCR拮抗剂的小分子文库中筛选抗埃博拉病毒抑制剂，基于结构-活性关系（SAR）优先考虑和化学修饰最有效的抑制剂，以提高效力和选择性。(2)在感染性试验中筛选先导抑制剂候选物 并研究EBOV抑制剂的作用机制（MOA）。(3)选择具有体外ADME特性的EBOV抑制剂，适用于静脉注射和口服给药。

 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.