A high throughput screen for TMPRSS2 expression identifies FDA‐approved and clinically advanced compounds that can limit SARS‐CoV‐2 entry

SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for global pandemic of COVID-19 disease. The Spike (S) protein attaches to host lung epithelial cells through cell surface receptor ACE2, a process dependent on proteases including TMPRSS2. Here, we identified small molecules that can reduce expression TMPRSS2 using 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear most potent agents, reducing endogenous at sub-micromolar concentrations. These effects be mediated by drug-induced alteration in stability. We further demonstrate modulates levels proteasomal-mediated degradation involves E3 ubiquitin ligase component DDB1- CUL4-associated factor 1 (DCAF1). Finally, exposed halofuginone, concentrations drug known achievable human plasma, demonstrated marked resistance pseudoviral infection. Given safety pharmacokinetic data already available compounds our screen, these results should help expedite rational design trials designed combat