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 K Nuñez; 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

doi:10.1038/s41556-021-00821-8

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

Nat Cell Biol. 2022 Jan;24(1):24-34. doi: 10.1038/s41556-021-00821-8. Epub 2022 Jan 13.

Authors

Avi J Samelson^{1

2}, Quang Dinh Tran^{3

4}, Rémy Robinot⁵, Lucia Carrau⁶, Veronica V Rezelj³, Alice Mac Kain^{3

4}, Merissa Chen^{1

2}, Gokul N Ramadoss^{7

8}, Xiaoyan Guo^{1

2}, Shion A Lim^{9

10}, Irene Lui⁹, James K Nuñez^{11

12}, Sarah J Rockwood⁷, Jianhui Wang¹³, Na Liu¹³, Jared Carlson-Stevermer¹⁴, Jennifer Oki¹⁴, Travis Maures¹⁴, Kevin Holden¹⁴, Jonathan S Weissman^{11

12

15

16}, James A Wells^{2

9

11}, Bruce R Conklin^{7

11

17

18}, Benjamin R TenOever⁶, Lisa A Chakrabarti⁵, Marco Vignuzzi³, Ruilin Tian^{19

20

21}, Martin Kampmann^{22

23

24}

Affiliations

¹ Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.
² Chan-Zuckerberg Biohub, San Francisco, CA, USA.
³ Viral Populations and Pathogenesis Unit, Institut Pasteur, Paris, France.
⁴ École Doctorale BioSPC, Université de Paris, Sorbonne Paris Cité, Paris, France.
⁵ Institut Pasteur, CIVIC Group, Virus and Immunity Unit, Université de Paris, Paris, France.
⁶ Microbiology Department, NYU-Langone, New York, NY, USA.
⁷ Gladstone Institutes, San Francisco, CA, USA.
⁸ Biomedical Sciences PhD Program, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Department of Antibody Engineering, Genentech Inc., San Francisco, CA, USA.
¹¹ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
¹² Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.
¹³ School of Medicine, Southern University of Science and Technology, Shenzhen, China.
¹⁴ Synthego Corporation, Redwood City, CA, USA.
¹⁵ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
¹⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, USA.
¹⁷ Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA. [email protected].
²⁰ Chan-Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
²¹ School of Medicine, Southern University of Science and Technology, Shenzhen, China. [email protected].
²² Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA. [email protected].
²³ Chan-Zuckerberg Biohub, San Francisco, CA, USA. [email protected].
²⁴ Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. [email protected].

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. Here we show 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 therapeutic target for COVID-19.

Publication types

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

MeSH terms

Angiotensin-Converting Enzyme 2 / drug effects
Angiotensin-Converting Enzyme 2 / metabolism*
Antiviral Agents / pharmacology*
COVID-19 / metabolism
COVID-19 / virology
COVID-19 Drug Treatment
Cell Line
Epithelial Cells / metabolism
Epithelial Cells / virology*
Humans
Membrane Glycoproteins / metabolism
SARS-CoV-2 / drug effects
SARS-CoV-2 / metabolism*
SARS-CoV-2 / pathogenicity
Transcription Factors / drug effects*
Transcription Factors / metabolism

Substances

Antiviral Agents
BRD2 protein, human
Membrane Glycoproteins
Transcription Factors
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding