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Novel Therapeutics for Neurotropic Alphaviruses

嗜神经甲病毒的新疗法

基本信息

批准号：
8303318
负责人：
DAVID J MILLER
金额：
$ 92.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8303318
关键词：
Abbreviations Actinobacteria class Affinity Chromatography Alkaline Phosphatase Alphavirus Anti-Infective Agents Antiviral Agents Arboviruses Area Artificial Membranes Astrocytes Biochemical Biological Assay Biological Factors Bioterrorism Bunyaviridae Categories Cell Culture Techniques Cell Membrane Permeability Cellular Assay Central Nervous System Infections Chemicals Chikungunya virus Combined Modality Therapy Culicidae Cultured Cells Dengue Virus Development Dimethyl Sulfoxide Discipline Disease Disease Outbreaks Dose Drug Kinetics Eastern Equine Encephalitis Virus Encephalitis Encephalitis Viruses Epidemic Equine Encephalomyelitis Escape Mutant Evaluation Family Firefly Luciferases Flaviviridae Goals Health High Pressure Liquid Chromatography Human In Vitro Indian Ocean Individual Infection Inhibitory Concentration 50 Insecta La Crosse virus Lead Marines Measurement Metabolic Microbe Microglia Modification Molecular Target Mus National Institute of Allergy and Infectious Disease Neuraxis Neurology Neurons Neuroprotective Agents Nuclear Magnetic Resonance P-Glycoprotein Pathology Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Physiology Positioning Attribute Proteins Public Health Pyrroles RNA-Directed RNA Polymerase Regimen Research Personnel Rift Valley fever virus Series Sindbis Virus Solubility Source St. Louis Encephalitis Virus Structure Structure-Activity Relationship Surface Testing Thiophenes Togaviridae Toxic effect Validation Venezuelan Equine Encephalitis Virus Viral Viral Encephalitis Virulent Virus Virus Replication West Nile virus Western Equine Encephalitis Virus Yellow fever virus analog base clinical efficacy cytotoxicity design effective therapy efficacy evaluation enzyme activity experience high throughput screening human disease improved in vitro activity in vivo innovation liquid chromatography mass spectrometry member microbial neurotropic novel novel strategies novel therapeutics particle pathogen pre-clinical prevent response small molecule small molecule libraries treatment strategy treatment trial vaccine development virology

项目摘要

DESCRIPTION (provided by applicant): Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses are transmitted by mosquitoes, cause serious and potentially fatal central nervous system infections in humans, and are considered NIAID Category B Priority Pathogens due to their potential misuse as bioterrorism agents. Although vaccine development is in progress for several alphaviruses, there is an urgent and pressing need for broadly active antiviral agents against these virulent pathogens. Studies with experimental alphavirus encephalitis in mice have shown that while neurons are damaged directly by virus, uninfected neurons are also damaged via bystander mechanisms that involve altered homeostatic and neuroprotective functions of microglial cells or astrocytes. Thus, we hypothesize that combination therapy that directly targets virus replication and enhances neuroprotective responses will provide synergistic benefit in viral encephalitis. To identify and develop new antivirals to test this hypothesis, we recently screened a chemically defined small molecule library and identified a thieno[3,2-b]pyrrole compound that has potent activity against neurotropic alphaviruses in culture. Furthermore, a limited structure-activity relationship analysis with twenty structurally related analogs identified six additional compounds with enhanced in vitro activity. In addition, to explore the innovative use of natural products as a source for novel antivirals, we analyzed a series of extracts derived from marine actinomycetes and identified several that contained potent activity against alphaviruses. We are currently positioned to rapidly and efficiently move candidate antivirals through preclinical development, and we have assembled a team of experienced investigators with diverse expertise in the fields of virology, neurology, pathology, physiology, and medicinal chemistry to accomplish this task. The long-term goals of this highly collaborative project are to develop effective and broadly active therapies for encephalitis caused by neurotropic alphaviruses and related arboviruses. The specific aims of this proposal are: (1) targeted chemical modification of lead antiviral compounds, based on the initial structure-activity relationship analysis, to enhance potency, reduce toxicity, improve solubility and metabolic stability, and optimize membrane permeability; (2) identify molecular target(s) responsible for their antiviral activity; (3) analyze the in vivo pharmacokinetics and efficacy of candidate antivirals, including combination treatment with neuroprotective agents; and (4) isolate and characterize novel compounds with antiviral activity derived from marine microbes.

描述(申请人提供)：嗜神经性甲型病毒，如西部、东部和委内瑞拉的马脑炎病毒，通过蚊子传播，在人类中引起严重的和潜在的致命的中枢神经系统感染，由于它们可能被误用为生物恐怖主义制剂，被认为是NIAID B类优先病原体。尽管针对几种甲型病毒的疫苗开发正在进行中，但迫切需要广泛有效的抗病毒药物来对抗这些毒力强的病原体。对小鼠实验性甲型病毒性脑炎的研究表明，虽然神经元直接受到病毒的损害，但未感染的神经元也会通过旁观者机制受到损害，这种机制涉及小胶质细胞或星形胶质细胞的稳态和神经保护功能的改变。因此，我们假设，直接针对病毒复制和增强神经保护反应的联合治疗将在病毒性脑炎中提供协同效益。为了确定和开发新的抗病毒药物来验证这一假说，我们最近筛选了一个化学定义的小分子文库，并在培养中鉴定了一种硫代并[3，2-b]吡咯化合物，它对嗜神经性甲型病毒具有强大的活性。此外，对20个结构相关的类似物进行了有限的构效关系分析，确定了另外6个具有增强体外活性的化合物。此外，为了探索天然产物作为新型抗病毒药物来源的创新用途，我们分析了一系列来自海洋放线菌的提取物，并确定了几种含有强大抗甲型病毒活性的提取物。我们目前的定位是通过临床前开发快速有效地转移候选抗病毒药物，我们已经组建了一支经验丰富的研究团队，他们在病毒学、神经学、病理学、生理学和药物化学领域具有不同的专业知识来完成这项任务。这一高度合作的项目的长期目标是为嗜神经性甲型病毒和相关虫媒病毒引起的脑炎开发有效和广泛活跃的治疗方法。这项建议的具体目的是：(1)以初步构效关系分析为基础，对铅类抗病毒化合物进行靶向化学修饰，以增强效力、降低毒性、改善溶解性和代谢稳定性，并优化膜通透性；(2)确定与其抗病毒活性有关的分子靶点(S)；(3)分析候选抗病毒药物的体内药代动力学和有效性，包括与神经保护剂的联合治疗；以及(4)分离并鉴定来自海洋微生物的具有抗病毒活性的新化合物。