Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

被引：78

作者：

Garcia, Gustavo, Jr. ^{[1
]}

Sharma, Arun ^{[2
,3
]}

Ramaiah, Arunachalam ^{[4
,5
]}

Sen, Chandani ^{[6
]}

Purkayastha, Arunima ^{[6
]}

Kohn, Donald B. ^{[6
,7
,8
]}

Parcells, Mark S. ^{[9
]}

Beck, Sebastian ^{[10
]}

Kim, Heeyoung ^{[11
]}

Bakowski, Malina A. ^{[12
]}

Kirkpatrick, Melanie G. ^{[12
]}

Riva, Laura ^{[12
]}

Wolff, Karen C. ^{[12
]}

Han, Brandon ^{[13
]}

Yuen, Constance ^{[13
]}

Ulmert, David ^{[1
,7
]}

Purbey, Prabhat K. ^{[14
]}

Scumpia, Phillip ^{[14
]}

Beutler, Nathan ^{[15
]}

Rogers, Thomas F. ^{[15
,16
]}

Chatterjee, Arnab K. ^{[12
]}

Gabriel, Guelsah ^{[10
]}

Bartenschlager, Ralf ^{[11
,17
,18
]}

Gomperts, Brigitte ^{[6
,7
,8
]}

Svendsen, Clive N. ^{[2
]}

Betz, Ulrich A. K. ^{[19
]}

Damoiseaux, Robert D. ^{[1
,7
,13
,20
]}

Arumugaswami, Vaithilingaraja ^{[1
,8
,13
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Smidt Heart Inst, Los Angeles, CA 90048 USA

[4] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA

[5] Univ Calif San Diego, Sect Cell & Dev Biol, San Diego, CA 92093 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Childrens Discovery & Innovat Inst, Mattel Childrens Hosp,Dept Pediat, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[9] Univ Delaware, Dept Anim & Food Sci, Dept Biol Sci, Newark, DE 19716 USA

[10] Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany

[11] Heidelberg Univ, Dept Infect Dis, Mol Virol, Heidelberg, Germany

[12] Calibr, 11119 North Torrey Pines Rd, La Jolla, CA 92037 USA

[13] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA

[14] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[15] Scripps Res Inst, Dept Immunol & Microbiol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[16] UC San Diego Sch Med, UC San Diego Div Infect Dis & Global Publ Hlth, La Jolla, CA 92093 USA

[17] German Ctr Infect Res, Heidelberg Partner Site, Heidelberg, Germany

[18] German Canc Res Ctr, Div Virus Associated Carcinogenesis, Heidelberg, Germany

[19] Merck KGaA, Darmstadt, Germany

[20] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA 90095 USA

来源：

CELL REPORTS | 2021年 / 35卷 / 01期

关键词：

RESPIRATORY SYNDROME CORONAVIRUS; KINASE INHIBITORS; VIRUS; INFECTION; CANCER; CELLS; MYOCARDITIS; ACTIVATION; THERAPY; PATHWAY;

D O I：

10.1016/j.celrep.2021.108940

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 torin 2 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.

引用

页数：17

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