Cell Reports (Apr 2021)
Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication
- 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
Affiliations
- Gustavo Garcia, Jr.
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Arun Sharma
- 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
- 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
- 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
- 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
- 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
- Department of Animal and Food Sciences, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Sebastian Beck
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Heeyoung Kim
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
- Malina A. Bakowski
- Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
- Melanie G. Kirkpatrick
- Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
- Laura Riva
- Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
- Karen C. Wolff
- Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
- Brandon Han
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Constance Yuen
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
- David Ulmert
- 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
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Phillip Scumpia
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Nathan Beutler
- Department of Immunology and Microbiology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
- Thomas F. Rogers
- 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
- Calibr, a division of Scripps Research Institute, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA
- Gülsah Gabriel
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Ralf Bartenschlager
- 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
- 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
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Ulrich A.K. Betz
- Merck KGaA, Darmstadt, Germany; Corresponding author
- Robert D. Damoiseaux
- 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; Corresponding author
- Vaithilingaraja Arumugaswami
- 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; Corresponding author
- Journal volume & issue
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Vol. 35,
no. 1
p. 108940
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.
