Marine Microbial Products as Novel Agents Against Neurotropic Arboviruses

海洋微生物产品作为对抗嗜神经虫媒病毒的新药物

• 批准号: 8082413
• 负责人: DAVID J MILLER
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082413
• 关键词: Alphavirus; Animal Model; Anti-Infective Agents; Antiviral Agents; Applications Grants; Arboviruses; Biological Assay; Biological Factors; Bunyaviridae; Categories; Cell Culture Techniques; Central Nervous System Infections; Chikungunya virus; Clinical; Clinical Distribution; Culicidae; Dengue Virus; Development; Disease; Disease Outbreaks; Drug Kinetics; Encephalitis Viruses; Epidemic; Equine Encephalomyelitis; Escape Mutant; Family; Flaviviridae; Fractionation; Future; Generations; Goals; Health; Human; In Vitro; Indian Ocean; Infection; Infection prevention; Insecta; La Crosse virus; Lead; Libraries; Marine Sediment; Marines; Mass Spectrum Analysis; Mass Vaccinations; Mediating; Microbe; Modification; Mus; NMR Spectroscopy; National Institute of Allergy and Infectious Disease; Neuraxis; Penetration; Pharmaceutical Preparations; Phase; Population; Preclinical Testing; Procedures; Production; Public Health; Replicon; Research; Research Project Grants; Research Proposals; Resolution; Rift Valley fever virus; Safety; Solubility; Source; St. Louis Encephalitis Virus; Structure; Structure-Activity Relationship; Therapy Clinical Trials; TimeLine; Togaviridae; Toxic effect; Vaccination; Vaccines; Validation; Viral; Viral Physiology; Virulence; Virulent; Virus; Virus Diseases; West Nile virus; Western Equine Encephalitis Virus; Yellow fever virus; analog; base; candidate identification; combat; design; effective therapy; high throughput screening; human disease; in vivo; member; microbial; microorganism; neurotropic; novel; novel strategies; novel therapeutics; particle; pathogen; pre-clinical; prevent; research study; vaccine development; vector

DESCRIPTION (provided by applicant): Mosquito-borne viruses, or arboviruses, are among the most important emerging pathogens worldwide with a significant potential impact on human health, and are also prominent components of the NIAID Category A, B, and C priority pathogens lists. The inclusion of many arboviruses as high priority pathogens is due in part to their virulence, the potential for vector-mediated dissemination, and the public concern regarding insect-borne viral infections. In addition, despite the worldwide impact of arboviruses, few effective treatments are currently available. The objective of this proposal is to use western equine encephalitis virus (WEEV), a category B arbovirus, to identify and develop novel antiviral compounds isolated from natural product extracts produced by marine sediment-derived microbes. Compounds derived from terrestrial and marine microorganisms have historically provided a rich source for novel therapeutics against a range of microorganisms, but have thus far been underutilized in the development of antiviral agents. We have already developed, validated, and employed a WEEV replicon-based assay to complete high-throughput screens against a library of >16,000 pre- fractionated extracts derived from a diverse array of marine microbial species. Furthermore, we have completed both analytical and preparative preliminary chromatographic fractionation procedures for two distinct extracts with validated antiviral activity. The specific aims of this proposal are designed to complete the isolation and functional characterization of active compounds from these two candidate extracts, including structural examination and initial viral target identification, and to expand the identification of microbe-derived natural products with anti-arboviral activity. The long term goals of this research project are to develop a wide range of antiviral compounds derived from marine microbes, characterize their structures and antiviral activities, and complete their preclinical testing in animal models of arbovirus-mediated disease, with the ultimate objective being clinical implementation of these candidate novel drugs. The experiments outlined in this exploratory project proposal will be used to establish the groundwork to accomplish these goals. PUBLIC HEALTH RELEVANCE: This study is designed to identify new drugs to treat central nervous system infections caused by potentially deadly viruses that are transmitted by insects. This research is important to public health because there are currently few effective medications to treat mosquito-borne viral infections, and preventative strategies such as vaccination are still in the developmental phases. In addition, routine vaccine distribution and use may be difficult to implement on a population-wide basis due to safety concerns with mass vaccination in the absence of an outbreak scenario. Therefore, the availability of effective medications to either treat established disease or prevent infection is a highly valuable component in the overall strategy to combat the potentially devastating diseases caused by these viruses.

描述（由申请人提供）：蚊媒病毒或虫媒病毒是全球最重要的新兴病原体之一，对人类健康具有重大潜在影响，也是NIAID a， B和C类优先病原体清单的重要组成部分。将许多虫媒病毒列为高度优先的病原体，部分原因是它们的毒性、媒介传播的可能性以及公众对虫媒病毒感染的关注。此外，尽管虫媒病毒在世界范围内造成影响，但目前很少有有效的治疗方法。本提案的目的是利用B类虫媒病毒西部马脑炎病毒（WEEV）鉴定和开发从海洋沉积物微生物产生的天然产物提取物中分离出来的新型抗病毒化合物。从陆地和海洋微生物中提取的化合物历来为针对一系列微生物的新疗法提供了丰富的来源，但迄今为止在抗病毒药物的开发中尚未得到充分利用。我们已经开发、验证并采用了一种基于WEEV复制的检测方法，对来自多种海洋微生物物种的16000个预分离提取物进行高通量筛选。此外，我们已经完成了两种具有抗病毒活性的不同提取物的分析和制备初步色谱分离程序。本课题的具体目的是完成这两种候选提取物中活性化合物的分离和功能表征，包括结构检测和初始病毒靶点鉴定，并扩大对具有抗病毒活性的微生物来源天然产物的鉴定。本研究项目的长期目标是开发从海洋微生物中提取的多种抗病毒化合物，表征其结构和抗病毒活性，并在虫媒病毒介导疾病的动物模型中完成临床前试验，最终目标是这些候选新药的临床应用。本探索性项目提案中概述的实验将用于建立实现这些目标的基础。