Published anti-SARS-CoV-2 in vitro hits share common mechanisms of action that synergize with antivirals.

The global efforts in the past year have led to the discovery of nearly 200 drug repurposing candidates for COVID-19. Gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. Following bioinformatics analyses revealed that the expression of these genes is associated with COVID-19 patient severity and has predictive power on anti-SARS-CoV-2 efficacy in vitro. Monensin, a top new compound that regulates these genes, was further confirmed as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. Interestingly, drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics could be centered around combinations of targeting these processes and viral proteins.