Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.
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DOI：
10.1016/j.celrep.2021.108940
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发表时间：
2021-04-06
期刊：
影响因子：
8.8
通讯作者：
Arumugaswami V
中科院分区：
文献类型：
--
作者：
Garcia G Jr;Sharma A;Ramaiah A;Sen C;Purkayastha A;Kohn DB;Parcells MS;Beck S;Kim H;Bakowski MA;Kirkpatrick MG;Riva L;Wolff KC;Han B;Yuen C;Ulmert D;Purbey PK;Scumpia P;Beutler N;Rogers TF;Chatterjee AK;Gabriel G;Bartenschlager R;Gomperts B;Svendsen CN;Betz UAK;Damoiseaux RD;Arumugaswami V
SARS-CoV-2目前已引发COVID-19全球健康危机。我们开发了一个中等通量的药物筛选系统，并确定了一个小分子库的34 430蛋白激酶抑制剂，能够抑制SARS-CoV-2在人类上皮细胞的细胞病变效应。这些药物抑制剂处于临床试验的不同阶段。我们检测了参与细胞信号通路mTOR-PI 3 K-AKT、ABL-BCR/MAPK和DNA损伤反应的关键蛋白，这些蛋白对SARS-CoV-2感染至关重要。基于药物-蛋白质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berzosertib和torin 2。Berzosertib在多种细胞类型中表现出对SARS-CoV-2的有效抗病毒活性，并在进入后阶段阻断复制。Berzosertib也抑制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，以限制冠状病毒复制作为宿主导向疗法治疗COVID-19及以后，以及提供了一个重要的机制，宿主-病原体相互作用。激酶抑制剂筛选鉴定出34种具有抗SARS-CoV-2活性的化合物抑制剂靶向mTOR-PI 3 K-AKT和DNA损伤反应（DDR）信号通路ATR激酶抑制剂berzosertib阻断SARS-CoV-1、SARS-CoV-2和MERS-CoV感染。筛选药物化合物库并鉴定SARS-CoV-2特异性抗病毒剂。这些药物已被证明可以调节细胞信号级联，包括mTOR-PI 3 K-AKT和DNA损伤反应（DDR）途径。一种高效的候选药物berzosertib阻断了多种冠状病毒，如SARS-CoV-1，SARS-CoV-2和MERS-CoV，从而提供了一种潜在的治疗COVID-19的药物。
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. Kinase inhibitor screen identified 34 compounds with anti-SARS-CoV-2 activity Inhibitors targeted mTOR-PI3K-AKT and DNA-damage response (DDR) signaling pathways ATR kinase inhibitor berzosertib blocked SARS-CoV-1, SARS-CoV-2, and MERS-CoV infection Treatment with berzosertib blocks SARS-CoV-2 at post-entry level in epithelial cells Garcia et al. screen a library of drug compounds and identify SARS-CoV-2-specific antiviral agents. These drugs have been shown to modulate cellular signaling cascades, including mTOR-PI3K-AKT and DNA-damage response (DDR) pathways. A highly effective drug candidate, berzosertib, blocked multiple coronaviruses, such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, thus providing a potential therapeutic against COVID-19.
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