- Garcia, Gustavo;
- Sharma, Arun;
- Ramaiah, Arunachalam;
- Sen, Chandani;
- Purkayastha, Arunima;
- Kohn, Donald B;
- Parcells, Mark S;
- Beck, Sebastian;
- Kim, Heeyoung;
- Bakowski, Malina A;
- Kirkpatrick, Melanie G;
- Riva, Laura;
- Wolff, Karen C;
- Han, Brandon;
- Yuen, Constance;
- Ulmert, David;
- Purbey, Prabhat K;
- Scumpia, Phillip;
- Beutler, Nathan;
- Rogers, Thomas F;
- Chatterjee, Arnab K;
- Gabriel, Gülsah;
- Bartenschlager, Ralf;
- Gomperts, Brigitte;
- Svendsen, Clive N;
- Betz, Ulrich AK;
- Damoiseaux, Robert D;
- Arumugaswami, Vaithilingaraja
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.