Core F – High-Throughput Screening

项目摘要-核心F 冠状病毒病（COVID-19）大流行对公共卫生和 全球经济在没有有效手段控制严重急性呼吸道病毒2型（SARS- 新冠病毒（COV-2）是COVID-19的病原体，新感染人数于二零二零年初激增。不到 两年来，有2.3亿多人受到感染，导致470多万人死亡。缺乏 有效的抗病毒对策在很大程度上导致了公共卫生组织无法阻止 SARS-CoV-2的最初传播。虽然目前有有效的疫苗，但关键因素，如疫苗 犹豫不决和SARS-CoV-2变种的增加能够逃避自然和疫苗诱导的免疫， 我们的能力有限，无法减少新的SARS-CoV-2病例的传播，并结束目前的大流行。COVID- 19大流行强调迫切需要有效的抗病毒对策来限制传播， 当前和未来病毒威胁的严重性。口服直接作用的抗病毒药物（DAA）将提供一个有价值的 阻止COVID-19的战争武器。抗病毒对策开发中心的目标 (AC/DC）将确定和开发DAA疗法，以减轻当前和未来的病毒威胁。履行这一 目的和识别新的DAA化学型，AC/DC高通量筛选（HTS）核心（核心F）将 针对所调查的各种病原体开展高通量筛查活动， AC/DC。基于我们在药物发现方面的专业知识和先前在口服药物开发和开发方面的成功经验， 可用的抗病毒药物，如莫努匹拉韦/EIDD-2801、EIDD-2749、GS-621763、GHP-88309、ERDRP-0519和 AVG-233，核心F将在BSL 3条件下利用最先进的HTS设施来识别新的抗病毒攻击 AC/DC正在研究针对各种可能大流行的RNA病毒的候选物。核心F将 开展AC/DC研究项目，以验证、优化和验证用于HTS活动的检测试剂盒。 我们将实施全自动HTS协议，以筛选我们广泛的小分子库， 在AC/DC内进一步发展的新的热门支架（具体目标1）。在研究项目的试点研究中 1和3，我们已经开发和优化了使用雪松亨尼帕病毒（CedV）和 SARS-CoV-2荧光素酶报告病毒。然后，我们实现了这些HTS协议，并成功地完成了 针对CedV和SARS-CoV-2的筛选活动，确定了几个有前途的命中支架，用于未来 机理表征和合成优化。除了筛选，核心F将产生生物活性 由核心B创建的候选热门产品的新类似物的配置文件，以促进跨核心合作， 加快“命中-领先”开发的速度（具体目标2）。核心F还将收购并在新的 复合库，为AC/DC命中到铅管道的扩展提供额外的机制，确保 实现AC/DC的关键目标（具体目标3）。

Project Summary – Core F The coronavirus disease (COVID-19) pandemic has led to devastating impacts on public health and the global economy. Without effective means of controlling the spread of severe acute respiratory virus 2 (SARS- CoV-2), the etiological agent of COVID-19, the number of new infections exploded in early 2020. In less than two years, over 230 million individuals have been infected, leading to more than 4.7 million deaths. The lack of effective antiviral countermeasures contributed greatly to the inability of public health organizations to halt the initial spread of SARS-CoV-2. While efficacious vaccines are currently available, key factors, such as vaccine hesitancy and the rise of SARS-CoV-2 variants capable of escaping natural and vaccine induced immunity, have limited our ability decrease the spread of new SARS-CoV-2 cases and end the current pandemic. The COVID- 19 pandemic has underscored the urgent need for effective antiviral countermeasures to limit the spread and severity of current and future viral threats. Orally-available direct-acting antivirals (DAA) would provide a valuable weapon in the war to halt COVID-19. The objective of the Antiviral Countermeasure Development Center (AC/DC) will be to identify and develop DAA therapeutics to mitigate current and future viral threats. To fulfill this objective and identify new DAA chemotypes, the AC/DC High-Throughput Screening (HTS) Core (Core F) will perform high-throughput screening campaigns against the various pathogens of concern investigated within AC/DC. Building on our expertise in drug discovery and previous success in identifying and developing orally available antivirals, such molnupiravir/EIDD-2801, EIDD-2749, GS-621763, GHP-88309, ERDRP-0519, and AVG-233, Core F will utilize a state-of-the-art HTS facility under BSL3 conditions to identify new antiviral hit candidates against various RNA viruses of pandemic potential under investigation within AC/DC. Core F will work individual AC/DC research projects to miniaturize, optimize, and validate assays for use in HTS campaigns. We will implement fully automated HTS protocols to screen our extensive library of small molecules to identify new hit scaffolds for further development within AC/DC (specific aim 1). In pilot studies with Research Projects 1 and 3, we have developed and optimized fully automated HTS assays using Cedar henipavirus (CedV) and SARS-CoV-2 luciferase reporter viruses. We then implemented these HTS protocols and completed successful screening campaigns against CedV and SARS-CoV-2, identifying several promising hit scaffolds for future mechanistic characterization and synthetic optimization. In addition to screening, Core F will generate bioactivity profiles of new analogs of hit candidates created by Core B to promote cross-core cooperation to significantly increase the speed of hit-to-lead development (specific aim 2). Core F will also acquire and perform HTS on new compound libraries, providing an additional mechanism for expansion of the AC/DC hit-to-lead pipeline, ensuring that the key goals of AC/DC are fulfilled (specific aim 3).