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: 8495891
• 负责人: Arnab Basu
• 金额: $ 61.46万
• 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/8495891
• 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（由申请人提供）：埃博拉病毒（EBOV）导致非洲严重病毒出血发作的周期性暴发，感染患者死亡率很高。由于其高度感染性，EBOV被疾病控制与预防中心（CDC）归类为生物武器代理类别。当前，尚无FDA批准的疫苗或抗病毒药，可对EBOV感染有效。此外，EBOV感染的快速发展将几乎没有机会在感染人群中发展获得的免疫力。因此，迫切需要开发有效的抗病毒药，以应对EBOV爆发或生物恐怖主义攻击。 EBOV感染是由病毒和宿主细胞膜之间的融合引发的，该病毒细胞膜是由病毒包膜糖蛋白（GP）介导的。 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开始和建立感染至关重要。 EBOV进入的阻塞将导致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，该抑制剂可预防性地用于潜在的EBOV暴露群体或在感染后治疗。在对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（IC50 = 20？M）有效，并且选择性指数较低。潜在的抑制剂及其衍生物将得到进一步优化和以药物化学为特征，以提高其抗EBOV效力（IC50 <1？m）和选择性指数（SI> 10）。此外，我们将继续筛选大量分子，以搜索具有更高选择性的抑制剂，以提供新的入口点进行化学优化。研究小组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，初始生物学测定，作用研究机理和体外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）大学。伊利诺伊州（UIC）的伊利诺伊州将进行行动研究机理； 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进入抑制剂候选者，这些候选者将推进研究新药（IND）促进毒理学和安全药理学研究。因此，本应用程序的具体目的是：1。屏幕化合物库以识别EBOV进入的选择性非毒素抑制剂； 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。确定最初命中率系列的作用机理（MOA），并确定筛选命中率的优先级； 4.识别具有适用于i.v.的体外ADME特性的EBOV抑制剂和口服给药；和5。在EBOV感染的豚鼠模型中评估EBOV抑制剂。