Mary Wilson
Well-known member
Publication History: Accepted: March 12, 2021
Published:March 17, 2021
DOI: https://doi.org/10.1016/j.celrep.2021.108940
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PDF Format:
SUMMARY
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 4307 protein kinase inhibitors that were capable of inhibiting SARS-CoV-2 cytopathic effect in humanepithelial 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 post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and 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-pathogeninteractions.
https://www.cell.com/action/showPdf?pii=S2211-1247(21)00254-0
Published:March 17, 2021
DOI: https://doi.org/10.1016/j.celrep.2021.108940
- Gustavo Garcia Jr., 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, G?lsah Gabriel, Ralf Bartenschlager, Brigitte Gomperts, Clive N. Svendsen, Ulrich A.K. Betz, Robert D. Damoiseaux, Vaithilingaraja Arumugaswami
- 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
_________________________________________________________________________________
PDF Format:
SUMMARY
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 4307 protein kinase inhibitors that were capable of inhibiting SARS-CoV-2 cytopathic effect in humanepithelial 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 post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and 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-pathogeninteractions.
https://www.cell.com/action/showPdf?pii=S2211-1247(21)00254-0