tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Arun Sharma[SUP] 2 [/SUP], Arunachalam Ramaiah[SUP] 3 [/SUP], Chandani Sen[SUP] 4 [/SUP], Arunima Purkayastha[SUP] 4 [/SUP], Donald B Kohn[SUP] 5 [/SUP], Mark S Parcells[SUP] 6 [/SUP], Sebastian Beck[SUP] 7 [/SUP], Heeyoung Kim[SUP] 8 [/SUP], Malina A Bakowski[SUP] 9 [/SUP], Melanie G Kirkpatrick[SUP] 9 [/SUP], Laura Riva[SUP] 9 [/SUP], Karen C Wolff[SUP] 9 [/SUP], Brandon Han[SUP] 10 [/SUP], Constance Yuen[SUP] 10 [/SUP], David Ulmert[SUP] 11 [/SUP], Prabhat K Purbey[SUP] 12 [/SUP], Phillip Scumpia[SUP] 12 [/SUP], Nathan Beutler[SUP] 13 [/SUP], Thomas F Rogers[SUP] 14 [/SUP], Arnab K Chatterjee[SUP] 9 [/SUP], G?lsah Gabriel[SUP] 7 [/SUP], Ralf Bartenschlager[SUP] 15 [/SUP], Brigitte Gomperts[SUP] 5 [/SUP], Clive N Svendsen[SUP] 16 [/SUP], Ulrich A K Betz[SUP] 17 [/SUP], Robert D Damoiseaux[SUP] 18 [/SUP], Vaithilingaraja Arumugaswami[SUP] 19 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Arun Sharma[SUP] 2 [/SUP], Arunachalam Ramaiah[SUP] 3 [/SUP], Chandani Sen[SUP] 4 [/SUP], Arunima Purkayastha[SUP] 4 [/SUP], Donald B Kohn[SUP] 5 [/SUP], Mark S Parcells[SUP] 6 [/SUP], Sebastian Beck[SUP] 7 [/SUP], Heeyoung Kim[SUP] 8 [/SUP], Malina A Bakowski[SUP] 9 [/SUP], Melanie G Kirkpatrick[SUP] 9 [/SUP], Laura Riva[SUP] 9 [/SUP], Karen C Wolff[SUP] 9 [/SUP], Brandon Han[SUP] 10 [/SUP], Constance Yuen[SUP] 10 [/SUP], David Ulmert[SUP] 11 [/SUP], Prabhat K Purbey[SUP] 12 [/SUP], Phillip Scumpia[SUP] 12 [/SUP], Nathan Beutler[SUP] 13 [/SUP], Thomas F Rogers[SUP] 14 [/SUP], Arnab K Chatterjee[SUP] 9 [/SUP], G?lsah Gabriel[SUP] 7 [/SUP], Ralf Bartenschlager[SUP] 15 [/SUP], Brigitte Gomperts[SUP] 5 [/SUP], Clive N Svendsen[SUP] 16 [/SUP], Ulrich A K Betz[SUP] 17 [/SUP], Robert D Damoiseaux[SUP] 18 [/SUP], Vaithilingaraja Arumugaswami[SUP] 19 [/SUP]
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.