Inhibition of Cytomegalovirus Replication with Extended Half-Life Synthetic Ozonides [Antiviral Agents]

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro, but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse CMV (MCMV) in vivo. Screening of four ozonides against HCMV Towne pp28-luciferase recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting 50% viral growth (EC₅₀) was 9.8±0.2 µM, and cytotoxicity in non-infected human fibroblasts (CC₅₀) was 128.1±8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV. The combination of OZ418 and ganciclovir (GCV) was synergistic in HCMV inhibition in vitro. Virus inhibition by OZ418 occurred at early stage and was dependent on cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with reduction of HCMV-induced expression of pRb, E2F1 and CDKs 1, 2, 4, and 6. In a MCMV model, once daily oral administration of OZ418 had significantly improved efficacy against MCMV as compared to twice daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 compared to AS. In summary, ozonides are proposed as potential therapeutics, alone or in combination with GCV, for HCMV infection in humans.

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