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: 8302453
• 负责人: Arnab Basu
• 金额: $ 83.05万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302453
• 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; Screening procedure; 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; 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（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，感染患者死亡率很高。由于埃博拉病毒具有高度传染性，美国疾病控制与预防中心 (CDC) 将埃博拉病毒列为 A 类生物武器。目前，尚无 FDA 批准的可有效对抗 EBOV 感染的疫苗或抗病毒药物。此外，埃博拉病毒感染的快速发展几乎不为感染人群提供获得性免疫力的机会。因此，迫切需要开发有效的抗病毒药物来应对埃博拉病毒爆发或生物恐怖袭击。埃博拉病毒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至关重要。阻断埃博拉病毒进入将导致病毒在其生命周期早期的感染性受到抑制。我们的目标是开发 EBOV 感染的小分子抑制剂，可用于预防潜在的 EBOV 暴露人群或在感染后阶段进行治疗。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，它们对传染性 EBOV 具有活性（IC50 = 20 µM），并且选择性指数较低。潜在的抑制剂及其衍生物将通过药物化学进一步优化和表征，以提高其抗埃博拉病毒效力（IC50<1μM）和选择性指数（SI>10）。此外，我们将继续筛选大量分子，寻找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感染评估； 3）大学。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。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研究性新药 (IND)，从而实现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力和选择性并验证其抗病毒活性； 3.确定初始热门系列的作用机制（MOA）并优先筛选热门； 4.鉴定具有适合静脉注射的体外 ADME 特性的 EBOV 抑制剂。和口服给药； 5. 在 EBOV 感染的豚鼠模型中评估 EBOV 抑制剂。