Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice.

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients. Author summary: Antivirals targeting SARS-CoV-2 are sorely needed. In this study, we screened a library of approximately 2000 drug compounds that have been used or are still used in the clinics. Among them, we identified clofoctol as an antiviral against SARS-CoV-2. This molecule is an antibacterial drug used for the treatment of bacterial respiratory tract infections and it was further investigated due to its safety profile and its properties to accumulate in the lungs. We further demonstrated that, in vivo, this compound reduces inflammatory gene expression and lowers pulmonary pathology. The antiviral and anti-inflammatory properties of clofoctol, associated with its safety profile and unique pharmacokinetic properties make a strong case for proposing clofoctol as an affordable therapeutic candidate for the treatment of COVID-19 patients. [ABSTRACT FROM AUTHOR]