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.

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 / drug therapy
  • COVID-19 / metabolism
  • COVID-19 / virology
  • 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