BIOSAFETY LEVEL 4 CORE

生物安全 4 级核心

• 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
• 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

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）和马尔堡病毒（MARV）列为A类优先病原体。EBOV和MARV在人类和非人灵长类动物中引起严重且通常致命的出血热，对于某些物种或毒株如EBOV扎伊尔株和MARV安哥拉株，病死率高达90%。目前，对于由自然爆发、实验室事故或故意滥用引起的EBOV感染，还没有批准的主动或被动治疗方式。因此，鉴定可开发成药物的丝状病毒IFN拮抗剂和VP 30功能的有效小分子抑制剂将具有高度意义。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VP 30功能的小分子抗丝状病毒疗法。这项工作的基础将是在细胞培养和动物模型中测试候选化合物对EBOV和MARV的抗病毒活性。此类检测必须按照选择代理规则在生物安全4级/动物生物安全4级（BSL- 4/ABSL-4）下进行。BSL 4核心将首先评估项目2和项目3在细胞培养中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价铅抑制剂，以确定最佳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验证。此外，核心B在命中中具有重要作用，以引导优化。其努力与项目1、2和3的努力将提供类似物结构与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）、体内疗效和安全性。此外，如项目1和3中所述，对MOA的理解在这些一流抑制剂的设计和未来开发中将非常重要，例如，减轻对靶向毒性的担忧。