BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.
Nat Cell Biol
; 24(1): 24-34, 2022 01.
Article
en En
| MEDLINE
| ID: mdl-35027731
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Antivirales
/
Factores de Transcripción
/
Células Epiteliales
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Enzima Convertidora de Angiotensina 2
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SARS-CoV-2
Límite:
Humans
Idioma:
En
Revista:
Nat Cell Biol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos