The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication

Posaconazole (PCZ) is a clinically approved drug used predominantly for prophylaxis and salvage therapy of fungal infections. Here, we report its previously undescribed anti-human cytomegalovirus (HCMV) activity. By antiviral assays we demonstrated that PCZ, along with other azolic antifungals, has a broad anti-HCMV activity being active against different strains including low-passage clinical isolates and strains resistant to viral DNA polymerase inhibitors. Using a pharmacological approach, we identified the inhibition of human cytochrome P450 51 (hCYP51) or lanosterol 14α demethylase, a cellular target of posaconazole in infected cells, as a mechanism of anti-HCMV activity of the drug. Indeed, hCYP51 expression was stimulated upon HCMV infection and the inhibition of its enzymatic activity by either a lanosterol analog (VFV) or PCZ decreased HCMV yield and infectivity of released virus particles. Importantly, we observed that the activity of the first line anti-HCMV drug ganciclovir was tenfold boosted by PCZ and that GCV and PCZ act synergistically in inhibiting HCMV replication. Taken together, these findings suggest that this clinically approved drug deserves further investigation in the development of host-directed antiviral strategies as a candidate anti-HCMV drug with a dual antimicrobial effect.