BIOSAFETY LEVEL 4 CORE

生物安全 4 级核心

基本信息

批准号：
9264696
负责人：
Alexander Bukreyev
金额：
$ 49.76万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9264696
关键词：
Aerosols Agreement Angola Animal Model Animals Antiviral Agents Arboviruses Biological Availability Bioterrorism Case Fatality Rates Categories Cavia Cell Culture Techniques Centers for Disease Control and Prevention (U.S.)Collection Democratic Republic of the Congo Development Diagnostic Disease Outbreaks Doctor of Philosophy Dose Ebola virus Emergency Situation Emerging Communicable Diseases Enzymes Equipment Event Filovirus Frankfurt-Marburg Syndrome Virus Funding Future Genetic Transcription Goals Government Housing Human Image Immunity Immunology In Vitro Infection Infectious Diseases Research Institutes Interferons Investigation Laboratories Lead Methodology Methods Mission Modality Modeling Mus National Institute of Allergy and Infectious Disease Oral Pharmaceutical Preparations Population Public Health Research Resources Rodent Role Safety Senior Scientist Services Structure Sudan System Testing Therapeutic Toxic effect Training United States National Institutes of Health Vaccination Vaccines Viral Hemorrhagic Fevers Viral Proteins Virus Virus Diseases Work Zaire Ebola virus analog animal model development base biodefense biosafety level 4 facility biothreat career design experience hemorrhagic fever virus in vitro activity in vivo inhibitor/antagonist laboratory accident member nonhuman primate pathogen pre-clinical professor screening small molecule small molecule inhibitor therapeutic target tissue processing vaccine candidate vaccine development

项目摘要

The CDC and NIAID have classified Ebola virus (EBOV) and Marburg virus (MARV) as Category A priority pathogens. EBOV and MARV cause severe and often fatal hemorrhagic fever in humans and nonhuman primates with case fatality rates up to 90% for some species or strains such as EBOV Zaire and MARV strain Angola. There are presently no approved active or passive therapeutic modalities for EBOV infections resulting from a natural outbreak, laboratory accident, or deliberate misuse. Therefore, identification of effective small molecule inhibitors of filoviral IFN-antagonists and of VP30 function that can be developed into drugs would be of high significance. The goal of this Center Is to develop small molecule anti-filoviral therapeutics that target filoviralinterferon (IFN) antagonist functions and VP30 function. Fundamental to this effort will be the testing of candidate compounds for antiviral activity against EBOV and MARV in cell culture and in animal models. Such testing must be performed at Biosafety Level 4 / Animal Biosafety level 4 (BSL- 4/ABSL-4) in accordance with Select Agent rules. The BSL4 core will first evaluate the antiviral activity of compounds identified by Projects 2 and 3 in cell culture. Lead inhibitors will be further evaluated In the mouse and guinea pig models of EBOV or MARV Infections to identify the best preclinical development candidates. Therefore, Core B will provide the proof of concept for the antiviral activities of hit compounds isolated In Projects 2 and 3. Moreover, Core B has an Important role in the hit to lead optimization. Its efforts together with the efforts from Projects 1, 2 and 3 will provide the relationships between analog structure and four key features - anti-filovirus activity, In vitro ADME including potential oral bioavailability, in vivo efficacy and safety. Further, an understanding of the MOA, as outlined in Projects 1 and 3, will be very Important In the design and future development of these first-in-class inhibitors by, for example, alleviating concerns about target-based toxicity.

CDC和NIAID已将埃博拉病毒（EBOV）和Marburg病毒（MARV）分类为A类优先病原体。 EBOV和MARV在人类和非人类灵长类动物中引起严重且经常致命的出血热，某些物种或诸如Ebov Zaire和Marv菌株Angola等菌株的病例死亡率高达90％。目前，由于自然爆发，实验室事故或故意滥用，目前尚无对EBOV感染的主动或被动治疗方式。因此，可以鉴定有效的液态病毒IFN抗逆转录病毒和VP30功能的小分子抑制剂，可以将其发展为药物具有很高的意义。该中心的目的是开发针对fileviralinterferon（IFN）拮抗剂功能和VP30功能的小分子抗丝病毒疗法。这项工作的基础是在细胞培养和动物模型中测试针对EBOV和MARV的抗病毒活性的候选化合物。这种测试必须按照精选代理规则在生物安全水平4 /动物生物安全水平（BSL-4 / absl-4）上进行。 BSL4核心将首先评估细胞培养项目2和3鉴定的化合物的抗病毒活性。将在EBOV或MARV感染的小鼠和豚鼠模型中进一步评估铅抑制剂，以鉴定最佳的临床前发育候选者。因此，核心B将为项目2和3中隔离的HIT化合物的抗病毒活性提供概念验证。它的努力以及项目1、2和3的努力将提供模拟结构与四个关键特征之间的关系 - 抗纤毛病毒活动，体外ADME，包括潜在的口服生物利用度，体内功效和安全性。此外，对项目1和3中概述的对MOA的理解将在这些第一类抑制剂的设计和未来开发中非常重要，例如减轻对基于目标毒性的关注。