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

SARS-CoV-2 infection begins when the viral Spike protein binds to its cell-surface receptor, ACE2, on human cells. We performed a targeted CRISPRi screen to identify druggable pathways that influence Spike protein binding to human cells. Our findings reveal that the protein BRD2 is essential for ACE2 transcription in human lung epithelial cells and cardiomyocytes. Inhibitors of BRD2, currently being tested in clinical trials, effectively block ACE2 expression and prevent SARS-CoV-2 infection in human cells, including those from human nasal epithelia. Additionally, pharmacological inhibition of BRD2 using the drug ABBV-744 reduced SARS-CoV-2 replication in Syrian hamsters. We also discovered that BRD2 regulates the transcription of several other genes activated by SARS-CoV-2 infection, including those involved in the interferon response, which is crucial for the antiviral response. Overall, our results identify BRD2 as a key regulator of the host response to SARS-CoV-2 infection and suggest that targeting BRD2 could be a promising therapeutic strategy for COVID-19.