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被疾病控制和预防中心（CDC）列为A类生物武器制剂，因为它具有高度传染性。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感染的快速进展将为感染人群中产生获得性免疫提供很少的机会。因此，迫切需要开发有效的抗病毒药物来应对EBOV爆发或生物恐怖袭击。EBOV感染是由病毒和宿主细胞膜之间的融合引发的，这是由病毒包膜糖蛋白（GP）介导的。EBOV-GP和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启动和建立是必不可少的。阻断EBOV进入将导致在其生命周期早期抑制病毒感染性。我们的目标是开发EBOV感染的小分子抑制剂，其可用于潜在的EBOV暴露人群的预防性治疗或感染后治疗。在该项目的初步研究中，我们已经确定了八种不同化学型的EBOV进入抑制剂，它们对感染性EBOV具有活性（IC 50 = 20？M）并且具有低选择性指数。潜在的抑制剂及其衍生物将进一步优化，并通过药物化学来表征，以增加其抗EBOV效力（IC 50 <1？M）和选择性指数（SI> 10）。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。该研究团队代表了四个经验丰富的研究和药物发现/开发小组的合作努力; 1）Microbiotix，Inc.将进行药物化学、初始生物测定、作用机制研究和体外ADME评价; 2）西南生物医学研究基金会（SFBR）将进行体外和体内EBOV感染评价; 3）伊利诺伊大学芝加哥分校（UIC）将进行作用机制研究;和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种EBOV进入抑制剂候选药物，这些候选药物将进入试验性新药（IND），从而能够进行毒理学和安全药理学研究。因此，本申请的具体目的是：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.优化目标化合物的效价和选择性，验证其抗病毒活性; 3.确定初始命中系列的作用机制（MOA）并优先筛选命中; 4.鉴定具有适合于静脉内和口服给药的体外ADME性质的EBOV抑制剂;以及5.在EBOV感染的豚鼠模型中评价EBOV抑制剂。

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.