BIOSAFETY LEVEL 4 CORE

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。埃博拉病毒和马里病毒在人类和非人类灵长类动物中引起严重且往往致命的出血热，某些物种或毒株（如扎伊尔埃博拉病毒和安哥拉马里病毒毒株）的病死率高达90%。对于由自然暴发、实验室事故或故意误用引起的EBOV感染，目前尚无批准的主动或被动治疗方式。因此，寻找丝状病毒ifn拮抗剂和VP30功能的有效小分子抑制剂并开发成药物具有重要意义。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。此类测试必须在生物安全等级4/动物生物安全等级4 （BSL- 4/ABSL-4）下按照选择制剂规则进行。BSL4核心将首先在细胞培养中评估项目2和项目3鉴定的化合物的抗病毒活性。铅抑制剂将在EBOV或MARV感染的小鼠和豚鼠模型中进一步评估，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和项目3中分离的hit化合物的抗病毒活性提供概念证明。此外，核心B在hit to lead优化中发挥着重要作用。其与项目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），体内有效性和安全性。此外，如项目1和项目3所述，了解MOA对这些一流抑制剂的设计和未来开发非常重要，例如，减轻对靶向毒性的担忧。

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.