Novel Therapeutics for Neurotropic Alphaviruses

嗜神经甲病毒的新疗法

• 批准号: 8685098
• 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
• 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/8685098
• 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

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（由申请人提供）：神经性α病毒，例如西方，东部和委内瑞拉马匹脑炎病毒由蚊子传播，在人类中引起严重且潜在的致命性中枢神经系统感染，并被认为是由于其潜在的生物使用症患者而被视为NIAID类别的优先病原体。尽管几种α病毒正在进行疫苗的发育，但紧急而迫切需要针对这些有毒病原体的广泛活性抗病毒剂。小鼠实验性α病毒脑炎的研究表明，尽管神经元直接受到病毒的伤害，但未感染的神经元也通过旁观者机制损害了涉及微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，我们假设直接靶向病毒复制并增强神经保护反应的联合疗法将为病毒脑炎提供协同益处。为了识别和开发新的抗病毒药以检验这一假设，我们最近筛选了化学定义的小分子文库，并鉴定出一种[3,2-B]吡咯型化合物，该吡咯会在培养中具有有效的活性活性。此外，有限的结构活性关系分析与二十个结构相关的类似物鉴定出具有增强体外活性的六种其他化合物。此外，为了探索天然产物作为新抗病毒药的来源的创新使用，我们分析了一系列源自海洋放线菌的提取物，并确定了几种含有针对α病毒的有效活性的提取物。目前，我们可以通过临床前开发快速有效地移动候选抗病毒药物，并且我们组建了一支经验丰富的研究人员，在病毒学，神经病学，病理学，生理学和药物化学领域具有多种专业知识，以完成这项任务。这个高度协作的项目的长期目标是为神经性α病毒和相关杂种病毒引起的脑炎开发有效且广泛的活性疗法。该提案的具体目的是：（1）基于初始结构 - 活性关系分析的铅化学修饰，以提高效力，降低毒性，提高溶解度和代谢稳定性，并优化膜通透性； （2）确定负责其抗病毒活性的分子靶标； （3）分析候选抗病毒药物的体内药代动力学和功效，包括与神经保护剂的联合治疗； （4）分离株和表征具有海洋微生物的抗病毒活性的新型化合物。

项目成果

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development.

宿主因素的操纵优化了小鼠西方马脑炎病毒感染的发病机制，用于抗病毒药物的开发。

• DOI: 10.1007/s13365-014-0297-8
• 发表时间: 2015-02
• 期刊: JOURNAL OF NEUROVIROLOGY
• 影响因子: 3.2
• 作者: Blakely, Pennelope K.;Delekta, Phillip C.;Miller, David J.;Irani, David N.
• 通讯作者: Irani, David N.

Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore.

• DOI: 10.1016/j.bmcl.2021.128171
• 发表时间: 2021-08-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Barraza SJ;Sindac JA;Dobry CJ;Delekta PC;Lee PH;Miller DJ;Larsen SD
• 通讯作者: Larsen SD

Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication.

• DOI: 10.1021/jm401330r
• 发表时间: 2013-11-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Sindac JA;Barraza SJ;Dobry CJ;Xiang J;Blakely PK;Irani DN;Keep RF;Miller DJ;Larsen SD
• 通讯作者: Larsen SD