Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Cell Rep. 2021 Apr 6;35(1):108940. doi: 10.1016/j.celrep.2021.108940. Epub 2021 Mar 18.
SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
SARS-CoV-2 目前引发了 COVID-19 全球健康危机。我们开发了一种中通量药物筛选系统，并鉴定出能够抑制人上皮细胞中 SARS-CoV-2 细胞病变效应的 430 种蛋白激酶抑制剂中的 34 种小分子文库。这些药物抑制剂处于临床试验的各个阶段。我们检测到参与细胞信号通路 mTOR-PI3K-AKT、ABL-BCR/MAPK 和 DNA 损伤反应的关键蛋白，这些蛋白对于 SARS-CoV-2 感染至关重要。基于药物-蛋白相互作用的二次筛选证实了具有抗 SARS-CoV-2 活性的化合物，如 ATR 激酶抑制剂伯佐替布和 torin2。伯佐替布在多种细胞类型中对 SARS-CoV-2 表现出强大的抗病毒活性，并在进入后阶段阻断复制。伯佐替布还抑制了 SARS-CoV-1 和中东呼吸综合征冠状病毒（MERS-CoV）的复制。我们的研究强调了关键的有前途的激酶抑制剂，作为一种宿主定向治疗，用于治疗 COVID-19 及以后的疾病，并提供了宿主-病原体相互作用的重要机制。
