Core F – High-Throughput Screening

项目摘要-核心F 冠状病毒病(新冠肺炎)大流行已对公众健康和 全球经济。如果没有有效的手段来控制严重急性呼吸道病毒2型(SARS- 新冠病毒(CoV-2)，新冠肺炎的病原体，新感染人数在2020年初呈爆炸式增长。在不到的时间里 两年来，已有超过2.3亿人感染，导致470多万人死亡。缺乏 有效的抗病毒对策极大地促进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可用，但关键因素，如疫苗 犹豫不决和SARS-CoV-2变种的兴起能够逃脱自然和疫苗诱导的免疫，已经 限制了我们的能力，减少了新的SARS-CoV-2病例的传播，结束了目前的大流行。COVID- 19大流行突出表明迫切需要有效的抗病毒对策来限制传播和 当前和未来病毒威胁的严重性。口服的直接作用抗病毒药物(DAA)将提供有价值的 阻止新冠肺炎的战争中的武器。抗病毒对策发展中心的目标 (AC/DC)将是识别和开发DAA疗法，以减轻当前和未来的病毒威胁。为了实现这一点 目标和确定新的DAA化学类型，AC/DC高通量筛选(HTS)核心(核心F)将 针对调查的各种关注病原体执行高通量筛查活动 交流/直流。以我们在药物发现方面的专业知识和之前在口腔识别和开发方面的成功为基础 现有的抗病毒药物，如Molnupiravir/EIDD-2801、EIDD-2749、GS-621763、GHP-88309、ERDRP-0519和 AVG-233，Core F将在BSL3条件下利用最先进的HTS设施来识别新的抗病毒药物 AC/DC内正在研究的针对各种具有大流行潜力的RNA病毒的候选药物。核心F将 致力于单个AC/DC研究项目，以微型化、优化和验证HTS活动中使用的分析方法。 我们将实施全自动HTS协议来筛选我们庞大的小分子文库以识别 在AC/DC内进一步开发的新的HIT支架(具体目标1)。在与研究项目的试点研究中 1和3，我们开发和优化了使用雪松黑尼帕病毒(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，并成功完成了 针对CedV和SARS-CoV-2的筛选活动，确定未来有希望的几个热门支架 机械表征和综合优化。除了筛选外，核心F还将产生生物活性 核心B创建了新的热门候选模拟简档，以显著促进跨核心合作 加快打头阵发展速度(具体目标2)。Core F还将收购并执行HTS在新的 复合库，为AC/DC击穿到引线管道的扩展提供了额外的机制，确保 实现交流/直流的关键目标(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).