The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19) 1 . The development of a vaccine is likely to take at least 12–18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose–response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod 2 – 4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19. A screen of the ReFRAME library of approximately 12,000 known drugs for antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified several candidate compounds with suitable activities and pharmacological profiles, which could potentially expedite the deployment of therapies for coronavirus disease 2019 (COVID-19).

中文翻译：

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通过大规模化合物再利用发现 SARS-CoV-2 抗病毒药物


2019 年严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的出现引发了严重肺炎样疾病 2019 冠状病毒病 (COVID-19) 的全球大流行1。疫苗的开发可能至少需要 12-18 个月，而新的抗病毒治疗剂的批准时间通常可能超过 10 年。因此，重新利用已知药物可以大大加速针对 COVID-19 的新疗法的部署。在这里，我们分析了一个药物库，其中包含约 12,000 种临床阶段或美国食品药品监督管理局 (FDA) 批准的小分子，用于识别 COVID-19 的候选治疗药物。我们报告了 100 种抑制 SARS-CoV-2 病毒复制的分子的鉴定，其中包括 21 种表现出剂量反应关系的药物。其中，13 种被发现具有与患者可能达到的治疗剂量相称的有效浓度，包括 PIKfyve 激酶抑制剂阿哌莫德 2 – 4 和半胱氨酸蛋白酶抑制剂 MDL-28170、Z LVG CHN2、VBY-825 和 ONO 5334。研究发现 MDL-28170、ONO 5334 和阿匹莫德可拮抗源自诱导多能干细胞的人肺细胞样细胞中的病毒复制，阿匹莫德还在原代人肺外植体模型中证明了抗病毒功效。由于本研究中确定的大多数分子已经进入临床，其已知的药理学和人体安全性特征将有助于加速这些药物治疗 COVID-19 的临床前和临床评估。 ReFRAME 库对大约 12,000 种已知的抗严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的抗病毒活性药物进行筛选，确定了几种具有合适活性和药理学特征的候选化合物，这可能会加快冠状病毒疾病疗法的部署2019 年（新冠肺炎 (COVID-19)）。