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BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2

Avi J. Samelson, Quang Dinh Tran, Rémy Robinot, Lucia Carrau, Veronica V. Rezelj, Alice Mac Kain, Merissa Chen, Gokul N. Ramadoss, Xiaoyan Guo, View ORCID ProfileShion A. Lim, Irene Lui, James Nunez, Sarah J. Rockwood, Jianhui Wang, Na Liu, View ORCID ProfileJared Carlson-Stevermer, View ORCID ProfileJennifer Oki, View ORCID ProfileTravis Maures, View ORCID ProfileKevin Holden, Jonathan S. Weissman, James A. Wells, Bruce R. Conklin, Benjamin R. TenOever, Lisa A. Chakrabarti, Marco Vignuzzi, Ruilin Tian, View ORCID ProfileMartin Kampmann
doi: https://doi.org/10.1101/2021.01.19.427194
Avi J. Samelson
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
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Quang Dinh Tran
3Institut Pasteur, Viral Populations and Pathogenesis Unit, CNRS UMR 3569, 75015 Paris, France
6École Doctorale BioSPC, Université de Paris, Sorbonne Paris Cité, 75006 Paris, France
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Rémy Robinot
4Institut Pasteur, CIVIC Group, Virus and Immunity Unit, CNRS UMR 3569, 75015 Paris, France
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Lucia Carrau
5Department of Microbiology, Icahn School of Medicine, New York, NY 10029
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Veronica V. Rezelj
3Institut Pasteur, Viral Populations and Pathogenesis Unit, CNRS UMR 3569, 75015 Paris, France
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Alice Mac Kain
3Institut Pasteur, Viral Populations and Pathogenesis Unit, CNRS UMR 3569, 75015 Paris, France
6École Doctorale BioSPC, Université de Paris, Sorbonne Paris Cité, 75006 Paris, France
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Merissa Chen
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
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Gokul N. Ramadoss
7Gladstone Institutes, San Francisco, 94158, CA, USA
8Biomedical Sciences PhD Program, University of California, San Francisco, CA, USA
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Xiaoyan Guo
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
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Shion A. Lim
9Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, 94158, USA
10Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USA
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  • ORCID record for Shion A. Lim
Irene Lui
9Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, 94158, USA
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James Nunez
11Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
12Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA
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Sarah J. Rockwood
7Gladstone Institutes, San Francisco, 94158, CA, USA
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Jianhui Wang
13School of Medicine, Southern University of Science and Technology, Shenzhen, China 518055
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Na Liu
13School of Medicine, Southern University of Science and Technology, Shenzhen, China 518055
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Jared Carlson-Stevermer
14Synthego Corporation, Redwood City, CA 94063, USA
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Jennifer Oki
14Synthego Corporation, Redwood City, CA 94063, USA
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Travis Maures
14Synthego Corporation, Redwood City, CA 94063, USA
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Kevin Holden
14Synthego Corporation, Redwood City, CA 94063, USA
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  • ORCID record for Kevin Holden
Jonathan S. Weissman
11Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
12Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA
15Whitehead Institute for Biomedical Research, Cambridge, 02142, USA
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James A. Wells
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
9Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, 94158, USA
11Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
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Bruce R. Conklin
7Gladstone Institutes, San Francisco, 94158, CA, USA
11Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
16Department of Ophthalmology, University of California, San Francisco, San Francisco, CA. 94158, USA
17Department of Medicine, University of California, San Francisco, San Francisco, CA, 94158, USA
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Benjamin R. TenOever
5Department of Microbiology, Icahn School of Medicine, New York, NY 10029
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Lisa A. Chakrabarti
4Institut Pasteur, CIVIC Group, Virus and Immunity Unit, CNRS UMR 3569, 75015 Paris, France
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Marco Vignuzzi
3Institut Pasteur, Viral Populations and Pathogenesis Unit, CNRS UMR 3569, 75015 Paris, France
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Ruilin Tian
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
13School of Medicine, Southern University of Science and Technology, Shenzhen, China 518055
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  • For correspondence: martin.kampmann@ucsf.edu tianrl@sustech.edu.cn
Martin Kampmann
1Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA
2Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA
18Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94158, USA
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  • ORCID record for Martin Kampmann
  • For correspondence: martin.kampmann@ucsf.edu tianrl@sustech.edu.cn
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Abstract

SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. We found that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a novel therapeutic target for COVID-19.

Competing Interest Statement

JCS, JO, TM and KH are employees and shareholders of Synthego Corporation.

Footnotes

  • Additional experiments, including validation of inhibition of SARS-CoV-2 replication by Brd2 inhibition in vivo in Syrian hamsters, and in vitro in reconstituted primary human nasal epithelia. Additional co-authors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2
Avi J. Samelson, Quang Dinh Tran, Rémy Robinot, Lucia Carrau, Veronica V. Rezelj, Alice Mac Kain, Merissa Chen, Gokul N. Ramadoss, Xiaoyan Guo, Shion A. Lim, Irene Lui, James Nunez, Sarah J. Rockwood, Jianhui Wang, Na Liu, Jared Carlson-Stevermer, Jennifer Oki, Travis Maures, Kevin Holden, Jonathan S. Weissman, James A. Wells, Bruce R. Conklin, Benjamin R. TenOever, Lisa A. Chakrabarti, Marco Vignuzzi, Ruilin Tian, Martin Kampmann
bioRxiv 2021.01.19.427194; doi: https://doi.org/10.1101/2021.01.19.427194
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BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2
Avi J. Samelson, Quang Dinh Tran, Rémy Robinot, Lucia Carrau, Veronica V. Rezelj, Alice Mac Kain, Merissa Chen, Gokul N. Ramadoss, Xiaoyan Guo, Shion A. Lim, Irene Lui, James Nunez, Sarah J. Rockwood, Jianhui Wang, Na Liu, Jared Carlson-Stevermer, Jennifer Oki, Travis Maures, Kevin Holden, Jonathan S. Weissman, James A. Wells, Bruce R. Conklin, Benjamin R. TenOever, Lisa A. Chakrabarti, Marco Vignuzzi, Ruilin Tian, Martin Kampmann
bioRxiv 2021.01.19.427194; doi: https://doi.org/10.1101/2021.01.19.427194

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