BIOSAFETY LEVEL 4 CORE

生物安全 4 级核心

基本信息

批准号：
8642744
负责人：
Alexander Bukreyev
金额：
$ 51.74万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642744
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 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 将埃博拉病毒 (EBOV) 和马尔堡病毒 (MARV) 列为 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常常致命的出血热，某些物种或毒株（例如 EBOV 扎伊尔毒株和 MARV 毒株安哥拉）的病死率高达 90%。目前还没有批准的主动或被动治疗方法来治疗自然爆发、实验室事故或故意滥用引起的埃博拉病毒感染。因此，鉴定可开发成药物的丝状病毒IFN拮抗剂和VP30功能的有效小分子抑制剂具有重要意义。该中心的目标是开发针对丝状病毒干扰素 (IFN) 拮抗剂功能和 VP30 功能的小分子抗丝状病毒疗法。这项工作的基础是在细胞培养物和动物模型中测试候选化合物对 EBOV 和 MARV 的抗病毒活性。此类测试必须根据 Select Agent 规则在生物安全 4 级/动物生物安全 4 级 (BSL-4/ABSL-4) 下进行。 BSL4 核心将首先评估项目 2 和 3 鉴定的化合物在细胞培养物中的抗病毒活性。将在 EBOV 或 MARV 感染的小鼠和豚鼠模型中进一步评估先导抑制剂，以确定最佳的临床前开发候选药物。因此，核心 B 将为项目 2 和 3 中分离的命中化合物的抗病毒活性提供概念证明。此外，核心 B 在先导化合物优化中具有重要作用。它的努力与项目 1、2 和 3 的努力一起将提供类似结构和四个关键特征之间的关系 - 抗丝状病毒活性、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，如项目 1 和 3 中所述，对 MOA 的理解对于这些一流抑制剂的设计和未来开发非常重要，例如可以减轻对基于靶标的毒性的担忧。