Novel filovirus entry inhibitors based on a pseudo-symmetrical biphenyl core

 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。尽管几种有希望的候选疫苗已被证明在激发宿主免疫反应和保护灵长类动物免受病毒感染方面是有效的，但疫苗接种所需的最短时间(至少一个月)和零星暴发的性质加强了开发有效的小分子抑制剂对抗丝状病毒感染的迫切需要。因此，迫切需要 发现和开发有效的抑制丝状病毒感染的药物。这些抑制剂被认为是 在丝状病毒暴发或生物恐怖袭击期间使用是至关重要的。这项申请定义了一项开发有效的小分子抑制剂的计划，它可以阻止EBOV和MARV进入宿主细胞。EBOV和MARV的进入是由单一的病毒糖蛋白(GP)介导的，这被认为是主要的治疗靶点之一。GP由GP1和GP2两个亚基组成，GP1负责受体结合和宿主趋向性，GP2介导病毒/细胞膜融合和病毒进入。我们使用了针对GP介导的病毒进入的HTS协议来筛选小分子文库，并且我们已经确定了抑制感染性EBOV/MARV进入的化合物(IC50值=25微米)。这些HIT化合物表现出对EBOV/MARV进入的选择性。这一第一阶段应用的总体目标是开发这些抑制剂作为潜在的抗丝病毒疗法。这项应用将集中于以下三个具体目标：(1)基于结构-活性关系(SARS)合成结构多样化的抗埃博拉SB699551热门系列类似物，以提高效力和选择性。(2)在感染性试验中验证候选的先导抑制剂，并研究EBOV/MARV抑制剂的作用机制。(3)筛选适合静脉注射的体外ADME性质的EBOV/MarV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. Although several promising vaccine candidates have been shown to be effective in eliciting host immune responses and to protect primates against viral infection, the minimal time required for vaccination (at least one month) and the sporadic nature of outbreaks reinforce the urgent need to develop potent, small molecule inhibitors against filoviral infections. Thus it is imperative to identify and develop potent inhibitors against filoviral infection. These inhibitors are considered to be of paramount importance for use during filoviral outbreaks or bioterrorist attacks. This application defines a plan to develop potent small molecule inhibitors, which block entry of EBOV and MARV into host cells. Entry of EBOV and MARV is mediated by a single viral glycoprotein (GP), which is considered one of the major therapeutic targets. GP consists of two subunits, GP1 and GP2; GP1 is responsible for receptor binding and host tropism, while GP2 mediates viral/cell membrane fusion and viral entry. We have used an HTS protocol targeting GP-mediated viral entry to screen a small molecule library, and we have identified compounds that inhibit entry of infectious EBOV/MARV (IC50 values =25 µM). These hit compounds exhibit selectivity for EBOV/MARV entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-filoviral therapeutics. This application will focus on the folloing three specific aims: (1) Synthesize structurally diverse analogs of the anti-Ebola SB699551 hit series 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/MARV inhibitors. (3) Select EBOV/MARV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.