학술논문
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication
Document Type
article
Author
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; Gülsah Gabriel; Ralf Bartenschlager; Brigitte Gomperts; Clive N. Svendsen; Ulrich A.K. Betz; Robert D. Damoiseaux; Vaithilingaraja Arumugaswami
Source
Cell Reports, Vol 35, Iss 1, Pp 108940- (2021)
Subject
Language
English
ISSN
2211-1247
Abstract
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 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.