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

A549 Cells Animals Antiviral Agents / pharmacology COVID-19 / metabolism 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 COVID-19 Drug Treatment
ATR kinase COVID-19 DNA-damage response pathway SARS-CoV-2 berzosertib high-throughput screen mTOR-PI3K-AKT pathway nucleoside analogs protein kinase inhibitors

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
06 04 2021
Historique:
received: 22 08 2020
revised: 26 01 2021
accepted: 12 03 2021
pubmed: 31 3 2021
medline: 20 4 2021
entrez: 30 3 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2021.108940 PMID: 33784499 PMC: PMC7969873
pubmed: 33784499
pii: S2211-1247(21)00254-0
doi: 10.1016/j.celrep.2021.108940
pmc: PMC7969873
pii:
doi:

Substances chimiques

Antiviral Agents 0
Isoxazoles 0
Pyrazines 0
berzosertib L423PRV3V3

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

108940

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY032149
Pays : United States
Organisme : NINR NIH HHS
ID : R21 NR010361
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL116273
Pays : United States

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests U.A.K.B. is an employee of Merck KGaA, Darmstadt, Germany. Berzosertib compound is licensed by Merck KGaA, Darmstadt, Germany. The other authors declare no competing financial interests.

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Auteurs

Gustavo Garcia (G)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Arun Sharma (A)

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Arunachalam Ramaiah (A)

Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, CA 92697, USA; Section of Cell and Developmental Biology, University of California, San Diego, San Diego, CA 92093, USA.

Chandani Sen (C)

UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

Arunima Purkayastha (A)

UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.

Donald B Kohn (DB)

UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.

Mark S Parcells (MS)

Department of Animal and Food Sciences, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.

Sebastian Beck (S)

Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.

Heeyoung Kim (H)

Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.

Malina A Bakowski (MA)

Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Melanie G Kirkpatrick (MG)

Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Laura Riva (L)

Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Karen C Wolff (KC)

Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Brandon Han (B)

California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Constance Yuen (C)

California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

David Ulmert (D)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.

Prabhat K Purbey (PK)

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Philip Scumpia (P)

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Nathan Beutler (N)

Department of Immunology and Microbiology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Thomas F Rogers (TF)

Department of Immunology and Microbiology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; UC San Diego Division of Infectious Diseases and Global Public Health, UC San Diego School of Medicine, La Jolla, CA 92093, USA.

Arnab K Chatterjee (AK)

Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Gülsah Gabriel (G)

Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.

Ralf Bartenschlager (R)

Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; German Center for Infection Research, Heidelberg partner site, Heidelberg, Germany; Division Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Brigitte Gomperts (B)

UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.

Clive N Svendsen (CN)

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Ulrich A K Betz (UAK)

Merck KGaA, Darmstadt, Germany. Electronic address: ulrich.betz@merckgroup.com.

Robert D Damoiseaux (RD)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rdamoiseaux@mednet.ucla.edu.

Vaithilingaraja Arumugaswami (V)

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: varumugaswami@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Eucaryotes › Animaux › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Cercopithecus › Cercopithecus aethiops › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Isoxazoles › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Coronavirus du syndrome respiratoire du Moyen-Orient › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrazines › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules Vero › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Antiviral drug screen identifies DNA-damage...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Traitements médicamenteux de la COVID-19 › Antiviral drug screen identifies DNA-damage...