Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication
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 Kumar Purbey, Philip O. Scumpia, Nathan Beutler, Thomas F. Rogers, Arnab K. Chatterjee, Gülşah Gabriel, Ralf Bartenschlager, Brigitte N. Gomperts, Clive N. Svendsen, Ulrich A. K. Betz, Robert Damoiseaux, Vaithilingaraja Arumugaswami
Abstract
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.