Virology Core

摘要 核心1(病毒学) MAVDA病毒学核心(MVC；核心1)已经建立，以提供基于细胞的感染分析 评估针对一系列基本病毒酶活性的HIT和先导化合物的有效性，如 由MAVDA项目负责人确定。与所有项目团队和核心密切合作，MVC 将在易受SARS感染的细胞中进行HIT和先导抗病毒化合物的早期剂量反应研究- 冠状病毒2型及相关冠状病毒。MVC还将确定细胞毒性和预测的治疗窗口 对于这些化合物。MVC提供的数据对药物发现流水线至关重要，并将为 中心迭代努力，以优化有希望的化合物，并形成做出是否通过的决定的基础 利用相关的体内模型将有前景的化合物向前推进到机理和动物研究中 新冠肺炎。MVC还增加了选择和识别具有耐药性的病毒变体的能力 可进一步告知铅化合物的行动模式，以及最大限度地提高对以下物质的抵抗力 病毒逃避治疗。筛查其他具有大流行重要性的病毒的能力，包括甲型病毒 和黄病毒，也将提供给项目组。 MVC将是一个单一实体，由查尔斯·M·赖斯(The Rockefeller University；RU)、斯蒂芬·P·莱斯(Stephen P. Goff和Yosef Sabo(哥伦比亚大学医学中心；CUMC)和David S.Perlin(发现和研究中心 创新，哈肯萨克子午线健康；CDI-HMH)。他们的联合实验室拥有数十年的专业知识 使用天然病毒分离株和工程报告系统开发和实施基于细胞的检测 来自冠状病毒、黄病毒、副粘液病毒、布尼亚病毒、托加病毒、费罗病毒和微微核糖核酸病毒家族的数十种病毒。 东道国机构的基础设施和对生物安全2级和3级优先事项的监管支持 病原体使用最先进的技术，具有从低到高的吞吐能力，将提供关键的第一次通过 以及跟进MAVDA项目1-6开发的化合物的临床前评估支持。这些努力 形成一个中心支柱，在此基础上可以快速高效地评估项目团队确定的化合物 针对各种病毒感染的抗病毒效力和体内潜在疗效，同时将细胞毒性降至最低。

Abstract Core 1 (Virology) The MAVDA Virology Core (MVC; Core 1) has been established to provide cell-based infection assays to evaluate the effectiveness of hit and lead compounds targeting a range of essential viral enzymatic activities as identified by MAVDA Project Leaders. Working in close collaboration with all Project Teams and Cores, the MVC will conduct early-stage dose-response studies of hit and lead antiviral compounds in cells susceptible to SARS- CoV-2 and related coronaviruses. The MVC will also determine cytotoxicity and predicted therapeutic windows for these compounds. The data provided by the MVC is essential for the drug discovery pipeline and will inform central iterative efforts to optimize promising compounds and form the basis for making go/no-go decisions for moving promising compounds forward into mechanistic and animal studies using relevant in vivo models of COVID-19. The MVC also has the added capability of selecting for and identifying resistant viral variants that may further inform modes of action for lead compounds, as well as efforts to maximize resistance barriers against viral escape from therapy. Capacity to screen additional viruses of pandemic importance, including alphaviruses and flaviviruses, will also be made available to Project Teams. The MVC will be a single entity headed by Charles M. Rice (The Rockefeller University; RU), Stephen P. Goff and Yosef Sabo (Columbia University Medical Center; CUMC) and David S. Perlin (Center for Discovery & Innovation, Hackensack Meridian Health; CDI-HMH). Their combined labs possess decades of expertise in developing and implementing cell-based assays using natural virus isolates and engineered reporter systems from dozens of viruses in the corona-, flavi-, paramyxo-, bunya-, toga-, filo-, and picorna- RNA virus families. The infrastructures of their host institutions and regulatory support for working with biosafety level 2 and 3 priority pathogens using state-of-the-art techniques with low to high-throughput capabilities will provide critical first pass and follow up pre-clinical evaluation support for compounds developed by MAVDA Projects 1-6. These efforts form a central pillar upon which compounds identified by Project teams can be rapidly and efficiently evaluated for antiviral potency and potential in vivo efficacy for a variety of viral infections while minimizing cellular toxicity.