Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

Cell Rep. 2021 Apr 6;35(1):108940. doi: 10.1016/j.celrep.2021.108940. Epub 2021 Mar 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antiviral Agents / pharmacology*
  • COVID-19 / drug therapy*
  • COVID-19 / metabolism
  • COVID-19 / pathology
  • Chlorocebus aethiops
  • DNA Damage*
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Isoxazoles / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Middle East Respiratory Syndrome Coronavirus / metabolism
  • Pyrazines / pharmacology*
  • SARS-CoV-2 / physiology*
  • Vero Cells
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Isoxazoles
  • Pyrazines
  • berzosertib