Developing small molecule therapeutics for Ebola hemorrhagic fever virus

描述（由申请人提供）：埃博拉病毒（EBOV）在非洲引起严重病毒性出血热的周期性爆发，感染患者的死亡率很高。EBOV因其高度传染性被疾病控制和预防中心（CDC）列为a类生物武器制剂。目前，没有FDA批准的疫苗或抗病毒药物对EBOV感染有效。此外，EBOV感染的快速进展将使受感染人群很少有机会产生获得性免疫。因此，迫切需要开发有效的抗病毒药物来应对埃博拉病毒的爆发或生物恐怖袭击。EBOV感染是由病毒包膜糖蛋白（GP）介导的病毒与宿主细胞膜融合引发的。EBOV-GP与宿主细胞表面受体分子之间的这种选择性相互作用对于感染的开始和建立至关重要。阻断EBOV的进入将导致在其生命周期早期抑制病毒的传染性。我们的目标是开发EBOV感染的小分子抑制剂，既可以用于预防潜在的EBOV暴露人群，也可以用于感染后时期的治疗。在该项目的初步研究中，我们已经鉴定出8种不同化学型的EBOV进入抑制剂，它们对感染性EBOV有活性(IC50 = 20 ？M)，选择性指数低。潜在抑制剂及其衍生物将进一步优化和药物化学表征，以提高其抗ebov效力(IC50 <1 ？M)，选择性指数（SI bbb10）。此外，我们将继续筛选大量分子，寻找具有更高选择性的抑制剂，为化学优化提供新的切入点。该研究小组由四个经验丰富的研究和药物发现/开发小组共同努力；1)Microbiotix, Inc.将进行药物化学、初步生物学分析、作用机制研究和体外ADME评估；2)由西南生物医学研究基金会（SFBR）进行体外和体内EBOV感染评估；3)伊利诺伊大学芝加哥分校（UIC）开展行动机制研究；4)哈佛医学院将进行ebov - gp受体结合研究。该提案的主要里程碑是选择2-3个EBOV进入抑制剂候选物，这些候选物将进入新药研究阶段，进行毒理学和安全药理学研究。因此，此应用程序的具体目标是：1。筛选化合物文库以鉴定EBOV进入的选择性非细胞毒性抑制剂；2. 优化命中化合物的效价和选择性，验证其抗病毒活性；3. 确定初始热门系列的作用机制（MOA），并优先筛选热门产品；4.鉴定具有适合静脉和口服给药的体外ADME特性的EBOV抑制剂；和5。评估EBOV抑制剂在EBOV感染豚鼠模型中的作用。

DESCRIPTION (provided by applicant): Ebola virus (EBOV) causes periodic outbreaks of severe viral hemorrhagic fevers in Africa with high mortality rates in infected patients. EBOV is classified as a Category A bioweapons agent by the Centers for Disease Control and Prevention (CDC) because of its highly infectious nature. Currently, there is no FDA approved vaccine or antiviral drug that is effective against EBOV infections. Moreover, rapid progression of EBOV infection will offer little opportunity for developing acquired immunity in an infected population. Therefore, there is a critical need for development of effective antivirals to respond to EBOV outbreak or bioterrorist attack. EBOV infection is initiated by the fusion between viral and host cell membranes, which is mediated by the viral envelope glycoprotein (GP). This selective interaction between EBOV-GP and host cell surface receptor molecules is essential for the initiation and establishment of the infection. Blocking of EBOV entry will lead to suppression of viral infectivity early in its life cycle. Our goal is to develop small molecule inhibitors of EBOV infection that can be used either prophylactically to a potentially EBOV exposed population or therapeutically during the post-infection period. In preliminary studies of this project, we have identified eight EBOV entry inhibitors of different chemotypes, which are active against infectious EBOV (IC50 = 20 ?M) and have low selectivity indices. The potential inhibitors and their derivatives will be further optimized and characterized by medicinal chemistry to increase their anti-EBOV potency (IC50 <1 ?M), and selectivity indices (SI>10). In addition, we will continue to screen a large number of molecules in a search for inhibitors with higher selectivity to provide new entry points for chemical optimization. The research team represents a collaborative effort by four experienced research and drug discovery/development groups; 1)Microbiotix, Inc. will conduct the medicinal chemistry, initial biological assays, mechanism of action studies and in vitro ADME evaluation; 2) Southwest Foundation for Biomedical Research (SFBR) will conduct the in vitro and in vivo EBOV infection evaluation; 3) Univ. of Illinois at Chicago (UIC) will conduct the mechanism of action studies; and 4) the Harvard Medical School will conduct the EBOV-GP-receptor binding studies. The major milestone of this proposal is to select 2-3 EBOV entry inhibitor candidates that will be advanced to Investigational New Drug (IND) enabling toxicology and safety pharmacology studies. Therefore the specific aims of this application are to: 1. Screen compound libraries to identify selective noncytotoxic inhibitors of EBOV entry; 2. Optimize the potency and selectivity of hit compounds and validate their antiviral activities; 3. Determine the mechanism of action (MOA) of the initial hit series and prioritize screening hits; 4.Identify EBOV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing; and 5. Evaluate EBOV inhibitors in a guinea pig model of EBOV infection.