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

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. T...

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Main Authors: Garcia, Gustavo, Jr. (Author) , Sharma, Arun (Author) , Ramaiah, Arunachalam (Author) , Sen, Chandani (Author) , Purkayastha, Arunima (Author) , Kohn, Donald B. (Author) , Parcells, Mark S. (Author) , Beck, Sebastian (Author) , Kim, Heeyoung (Author) , Bakowski, Malina A. (Author) , Kirkpatrick, Melanie G. (Author) , Riva, Laura (Author) , Wolff, Karen C. (Author) , Han, Brandon (Author) , Yuen, Constance (Author) , Ulmert, David (Author) , Purbey, Prabhat K. (Author) , Scumpia, Phillip (Author) , Beutler, Nathan (Author) , Rogers, Thomas F. (Author) , Chatterjee, Arnab K. (Author) , Gabriel, Gülsah (Author) , Bartenschlager, Ralf (Author) , Gomperts, Brigitte (Author) , Svendsen, Clive N. (Author) , Betz, Ulrich A. K. (Author) , Damoiseaux, Robert D. (Author) , Arumugaswami, Vaithilingaraja (Author)
Format: Article (Journal)
Language:English
Published: March 18, 2021
In: Cell reports
Year: 2021, Volume: 35, Issue: 1
ISSN:2211-1247
DOI:10.1016/j.celrep.2021.108940
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2021.108940
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124721002540
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Author Notes:Gustavo Garcia, Arun Sharma, Arunachalam Ramaiah, Chandani Sen, Arunima Purkayastha, Donald B. Kohn, Mark S. Parcells, Sebastian Beck, Heeyoung Kim, Malina A. Bakowski, Melanie G. Kirkpatrick, Laura Riva, Karen C. Wolff, Brandon Han, Constance Yuen, David Ulmert, Prabhat K. Purbey, Phillip Scumpia, Nathan Beutler, Thomas F. Rogers, Arnab K. Chatterjee, Gülsah Gabriel, Ralf Bartenschlager, Brigitte Gomperts, Clive N. Svendsen, Ulrich A.K. Betz, Robert D. Damoiseaux and Vaithilingaraja Arumugaswami

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520 |a 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. 
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