Tweet
Cell Rep
. 2021 Mar 18;108940.
doi: 10.1016/j.celrep.2021.108940. Online ahead of print.
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication
Gustavo Garcia Jr 1 , Arun Sharma 2 , Arunachalam Ramaiah 3 , Chandani Sen 4 , Arunima Purkayastha 4 , Donald B Kohn 5 , Mark S Parcells 6 , Sebastian Beck 7 , Heeyoung Kim 8 , Malina A Bakowski 9 , Melanie G Kirkpatrick 9 , Laura Riva 9 , Karen C Wolff 9 , Brandon Han 10 , Constance Yuen 10 , David Ulmert 11 , Prabhat K Purbey 12 , Phillip Scumpia 12 , Nathan Beutler 13 , Thomas F Rogers 14 , Arnab K Chatterjee 9 , G?lsah Gabriel 7 , Ralf Bartenschlager 15 , Brigitte Gomperts 5 , Clive N Svendsen 16 , Ulrich A K Betz 17 , Robert D Damoiseaux 18 , Vaithilingaraja Arumugaswami 19
Affiliations
- PMID: 33784499
- PMCID: PMC7969873
- DOI: 10.1016/j.celrep.2021.108940
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.
Keywords: ATR kinase; COVID-19; DNA-damage response pathway; SARS-CoV-2; berzosertib; high-throughput screen; mTOR-PI3K-AKT pathway; nucleoside analogs; protein kinase inhibitors.