The Artemisinin Derivative Artemisone Is a Potent Inhibitor of Human Cytomegalovirus Replication and Acts Synergistically with Approved and Experimental Antiviral Drugs

Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neuro-sensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently-available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The anti-malarial artemisinin derivative artesunate was shown to inhibit HCMV in-vitro, yet has demonstrated limited antiviral efficacy in-vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the new artemisinin derivative artemisone, which has been screened against malaria in human clinical studies, is a potent and non-cytotoxic inhibitor of HCMV. Artemisone demonstrated a ≥10-fold superior efficacy to that of artesunate, with a mechanism of action distinct from that of the viral DNA polymerase inhibitors. We have further evaluated the antiviral effect of artemisone when employed in 2-drug combinations, showing that in-vitro combination of artemisone with currently approved and new-experimental inhibitors of the viral DNA polymerase, terminase-complex, or the UL97 kinase, resulted in moderate-to-strong synergistic effects. Importantly, artemisone most effectively inhibited HCMV infection ex-vivo, further showing a synergistic activity with the viral UL97 inhibitor maribavir, in a clinically-relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings together with its apparent safety profile encourage clinical studies of artemisone as a new inhibitor against HCMV, and provide the basis for the use of artemisone in synergistically acting drug combinations, to enhance viral control, and reduce antiviral drug toxicities.