High-Throughput Screening for Drugs That Inhibit Papain-Like Protease in SARS-CoV-2
High-Throughput Screening for Drugs That Inhibit Papain-Like Protease in SARS-CoV-2
复制标题
DOI：
10.1177/2472555220963667
复制
发表时间：
2020-10-10
期刊：
影响因子：
3.1
通讯作者：
Spicer, Timothy P.
中科院分区：
文献类型：
--
作者：
Smith, Emery;Davis-Gardner, Meredith E.;Spicer, Timothy P.
2019年底出现的严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）引发了一场持续的全球大流行，感染可能导致致命的严重肺炎样疾病，称为2019冠状病毒病（COVID-19）。迄今为止，全球已报告了数百万例确诊病例和数十万例死亡病例，目前尚无预防或治疗该疾病的医学对策。据称疫苗的开发可能需要至少1-4年，而从抗病毒药物的命中发现到药物注册的典型时间轴是>10年。因此，重新定位已知药物可以显著加快COVID-19疗法的开发和部署。为了确定可以重新用作SARS-CoV-2抗病毒药物的治疗方法，我们开发并启动了一种基于细胞的高通量筛选，该筛选将必需的病毒木瓜蛋白酶样蛋白酶（PLpro）及其肽切割位点纳入荧光素酶互补测定中，以评估已知药物的疗效，包括约15，000种临床阶段或美国食品和药物管理局（FDA）批准的小分子。还检测了确认的抑制剂，以确定其细胞毒性特性。在这里，我们报告了四个临床相关的药物，表现出选择性抑制SARS-CoV-2病毒PLpro的鉴定。
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has triggered an ongoing global pandemic whereby infection may result in a lethal severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, millions of confirmed cases and hundreds of thousands of deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. The purported development of a vaccine could require at least 1-4 years, while the typical timeline from hit finding to drug registration of an antiviral is >10 years. Thus, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we developed and initiated a high-throughput cell-based screen that incorporates the essential viral papain-like protease (PLpro) and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or US Food and Drug Administration (FDA)-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Here, we report the identification of four clinically relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral PLpro.