Developing small molecule therapeutics for Ebola hemorrhagic fever virus

开发埃博拉出血热病毒的小分子疗法

• 批准号: 8681302
• 负责人: Arnab Basu
• 金额: $ 79.93万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681302
• 关键词: Affinity; Africa; Antiviral Agents; Binding; Biological; Biological Assay; Biomedical Research; Bioterrorism; Categories; Cavia; Cell Surface Receptors; Cell membrane; Centers for Disease Control and Prevention (U.S.); Chemicals; Chicago; Chimeric Proteins; DNA Sequence Rearrangement; Development; Disease Outbreaks; Dose; Ebola Hemorrhagic Fever; Ebola virus; Evaluation; Exhibits; FDA approved; Foundations; Frankfurt-Marburg Syndrome Virus; Glycoproteins; Goals; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; Human; Illinois; Immune response; In Vitro; Infection; Inhibitory Concentration 50; Investigational Drugs; Lead; Length; Libraries; Life Cycle Stages; Link; Liver Microsomes; Mediating; Membrane Fusion; Modeling; N-terminal; Nature; Oral; Paramyxovirus; Pathway interactions; Patients; Permeability; Persons; Pharmaceutical Chemistry; Pharmacology; Population; Primates; Property; Protein Isoforms; Proteins; Research; Safety; Series; Staging; Structure; Structure-Activity Relationship; Surface; Syndrome; Synthesis Chemistry; System; Systemic infection; T-20; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Tropism; Vaccination; Vaccines; Viral; Viral Hemorrhagic Fevers; Virion; Virus; Virus Diseases; Virus Inhibitors; acquired immunity; aerosolized; base; disorder prevention; disulfide bond; drug discovery; experience; hemorrhagic fever virus; high throughput screening; improved; in vivo; indexing; inhibitor/antagonist; medical schools; mortality; nonhuman primate; novel; protein protein interaction; receptor binding; screening; small molecule; small molecule libraries; vaccine candidate; virus development; weapons

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.

描述(申请人提供)：埃博拉病毒(EBOV)导致非洲周期性爆发严重的病毒性出血热，感染患者的死亡率很高。EBOV因其高度传染性而被疾病控制和预防中心(CDC)列为A类生物武器制剂。目前，还没有FDA批准的疫苗或抗病毒药物可以有效地对抗EBOV感染。此外，EBOV感染的快速发展将不会提供在感染人群中发展获得性免疫的机会。因此，迫切需要开发有效的抗病毒药物来应对EBOV暴发或生物恐怖袭击。EBOV感染是由病毒囊膜糖蛋白(GP)介导的病毒与宿主细胞膜的融合引起的。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，既可以预防潜在的EBOV暴露人群，也可以在感染后时期用于治疗。在本项目的初步研究中，我们鉴定了8种不同化学类型的EBOV进入抑制剂，它们对感染性EBOV(IC50=20M)具有活性，且选择性指数较低。潜在的抑制剂及其衍生物将进一步进行优化和药物化学表征，以提高它们的抗EBOV效力(IC50；1M)和选择性指数(SI&GT；10)。此外，我们还将继续筛选大量的分子，寻找选择性更高的缓蚀剂，为化学优化提供新的切入点。该研究团队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、初步生物检测、作用机制研究和体外ADME评估；2)西南生物医学研究基金会(SFBR)将进行体外和体内EBOV感染评估；3)Univ。伊利诺伊大学芝加哥分校(UIC)将进行作用机制研究；4)哈佛医学院将进行EBOV-GP受体结合研究。这项建议的主要里程碑是选择2-3个EBOV进入抑制剂候选，这些候选药物将进入能够进行毒理学和安全药理学研究的研究新药(IND)。因此，本申请的具体目的是：1.筛选化合物文库，以筛选选择性的非细胞毒性EBOV进入抑制剂；2.优化HIT化合物的效力和选择性，并验证其抗病毒活性；3.确定初始HIT系列的作用机制(MOA)并优先筛选HITS；4.筛选具有体外ADME特性的EBOV抑制剂，适合静脉注射。和口服剂量；以及5.在EBOV感染的豚鼠模型中评估EBOV抑制剂。