Your browser doesn't support javascript.
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.
Garcia, Gustavo; Sharma, Arun; Ramaiah, Arunachalam; Sen, Chandani; Purkayastha, Arunima; Kohn, Donald B; Parcells, Mark S; Beck, Sebastian; Kim, Heeyoung; Bakowski, Malina A; Kirkpatrick, Melanie G; Riva, Laura; Wolff, Karen C; Han, Brandon; Yuen, Constance; Ulmert, David; Purbey, Prabhat K; Scumpia, Philip; Beutler, Nathan; Rogers, Thomas F; Chatterjee, Arnab K; Gabriel, Gülsah; Bartenschlager, Ralf; Gomperts, Brigitte; Svendsen, Clive N; Betz, Ulrich A K; Damoiseaux, Robert D; Arumugaswami, Vaithilingaraja.
  • Garcia G; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Medicin
  • Parcells MS; Department of Animal and Food Sciences, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
  • Beck S; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
  • Kim H; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
  • Bakowski MA; Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Kirkpatrick MG; Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Riva L; Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Wolff KC; Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Han B; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yuen C; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 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.
  • Purbey PK; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Scumpia P; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Beutler N; Department of Immunology and Microbiology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 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.
  • Chatterjee AK; Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Gabriel G; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
  • 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.
  • 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 Medicin
  • Svendsen CN; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Betz UAK; Merck KGaA, Darmstadt, Germany. Electronic address: ulrich.betz@merckgroup.com.
  • 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
  • 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,
Cell Rep ; 35(1): 108940, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1157178
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrazines / Virus Replication / DNA Damage / SARS-CoV-2 / COVID-19 Drug Treatment / Isoxazoles Type of study: Diagnostic study / Prognostic study Topics: Traditional medicine Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.108940

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrazines / Virus Replication / DNA Damage / SARS-CoV-2 / COVID-19 Drug Treatment / Isoxazoles Type of study: Diagnostic study / Prognostic study Topics: Traditional medicine Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.108940