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

共 80 条

[31] Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial [J].

Konstantinopoulos, Panagiotis A. ;

Cheng, Su-Chun ;

Hendrickson, Andrea E. Wahner ;

Penson, Richard T. ;

Schumer, Susan T. ;

Doyle, L. Austin ;

Lee, Elizabeth K. ;

Kohn, Elise C. ;

Duska, Linda R. ;

Crispens, Marta A. ;

Olawaiye, Alexander B. ;

Winer, Ira S. ;

Barroilhet, Lisa M. ;

Fu, Siqing ;

McHale, Michael T. ;

Schilder, Russell J. ;

Farkkila, Anniina ;

Chowdhury, Dipanjan ;

Curtis, Jennifer ;

Quinn, Roxanne S. ;

Bowes, Brittany ;

D'Andrea, Alan D. ;

Shapiro, Geoffrey, I ;

Matulonis, Ursula A. .

LANCET ONCOLOGY, 2020, 21 (07) :957-968

[32] STITCH: interaction networks of chemicals and proteins [J].

Kuhn, Michael ;

von Mering, Christian ;

Campillos, Monica ;

Jensen, Lars Juhl ;

Bork, Peer .

NUCLEIC ACIDS RESEARCH, 2008, 36 :D684-D688

[33] Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication [J].

Kuss-Duerkop, Sharon K. ;

Wang, Juan ;

Mena, Ignacio ;

White, Kris ;

Metreveli, Giorgi ;

Sakthivel, Ramanavelan ;

Metal, Miguel A. ;

Munoz-Moreno, Raquel ;

Chen, Xiang ;

Krammer, Florian ;

Diamonds, Michael S. ;

Chen, Zhijian J. ;

Garcia-Sastre, Adolfo ;

Fontoura, Beatriz M. A. .

PLOS PATHOGENS, 2017, 13 (09)

[34] Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells [J].

Lan, Feng ;

Lee, Andrew S. ;

Liang, Ping ;

Sanchez-Freire, Veronica ;

Nguyen, Patricia K. ;

Wang, Li ;

Han, Leng ;

Yen, Michelle ;

Wang, Yongming ;

Sun, Ning ;

Abilez, Oscar J. ;

Hu, Shijun ;

Ebert, Antje D. ;

Navarrete, Enrique G. ;

Simmons, Chelsey S. ;

Wheeler, Matthew ;

Pruitt, Beth ;

Lewis, Richard ;

Yamaguchi, Yoshinori ;

Ashley, Euan A. ;

Bers, Donald M. ;

Robbins, Robert C. ;

Longaker, Michael T. ;

Wu, Joseph C. .

CELL STEM CELL, 2013, 12 (01) :101-113

[35] Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway [J].

Le Sage, Valerie ;

Cinti, Alessandro ;

Amorim, Raquel ;

Mouland, Andrew J. .

VIRUSES-BASEL, 2016, 8 (06)

[36] Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues [J].

Li, Meng-Yuan ;

Li, Lin ;

Zhang, Yue ;

Wang, Xiao-Sheng .

INFECTIOUS DISEASES OF POVERTY, 2020, 9 (01)

[37] A genome-wide genetic screen for host factors required for hepatitis C virus propagation [J].

Li, Qisheng ;

Brass, Abraham L. ;

Ng, Aylwin ;

Hu, Zongyi ;

Xavier, Ramnik J. ;

Liang, T. Jake ;

Elledge, Stephen J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (38) :16410-16415

[38] Marek's Disease Virus Disables the ATR-Chk1 Pathway by Activating STAT3 [J].

Lian, Xue ;

Bao, Chenyi ;

Li, Xueqi ;

Zhang, Xunhai ;

Chen, Hongjun ;

Jung, Yong-Sam ;

Qian, Yingjuan .

JOURNAL OF VIROLOGY, 2019, 93 (09)

[39] Using or abusing: viruses and the cellular DNA damage response [J].

Lilley, Caroline E. ;

Schwartz, Rachel A. ;

Weitzman, Matthew D. .

TRENDS IN MICROBIOLOGY, 2007, 15 (03) :119-126

[40] Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro [J].

Liu, Jia ;

Cao, Ruiyuan ;

Xu, Mingyue ;

Wang, Xi ;

Zhang, Huanyu ;

Hu, Hengrui ;

Li, Yufeng ;

Hu, Zhihong ;

Zhong, Wu ;

Wang, Manli .

CELL DISCOVERY, 2020, 6 (01)

← 1 2 3 4 5 6 7 8 →