Inhibition of Cytomegalovirus Replication with Extended-Half-Life Synthetic Ozonides

Area of Science:

• Virology
• Pharmacology
• Drug Discovery

Background:

• Artesunate (AS), an antimalarial, shows variable success against human cytomegalovirus (HCMV) in humans, possibly due to its short in vivo half-life.
• Novel synthetic ozonides were developed to overcome the pharmacokinetic limitations of AS.

Purpose of the Study:

• To evaluate the efficacy of novel synthetic ozonides against HCMV and mouse cytomegalovirus (MCMV).
• To compare the therapeutic potential of OZ418 with AS in preclinical models.

Main Methods:

• Screening of four ozonides against an HCMV recombinant identified OZ418.
• In vitro assays assessed OZ418's efficacy against HCMV, including ganciclovir-resistant strains, and its synergy with ganciclovir (GCV).
• In vivo studies utilized an MCMV mouse model to compare OZ418 and AS efficacy and pharmacokinetics.

Main Results:

• OZ418 demonstrated potent HCMV inhibition (EC50 = 9.8 ± 0.2 µM) with low cytotoxicity (CC50 = 128.1 ± 8.0 µM).
• OZ418 showed concentration-dependent inhibition of HCMV, including GCV-resistant isolates, and synergistic effects with GCV.
• In vivo, OZ418 exhibited superior efficacy against MCMV compared to AS, with a longer plasma half-life and higher unbound concentrations.

Conclusions:

• Synthetic ozonides, particularly OZ418, represent promising candidates for HCMV therapy.
• OZ418 demonstrates improved pharmacokinetic properties and efficacy over AS, suggesting potential as a standalone or combination therapy with GCV.