Atovaquone may be effective for the treatment of mpox (monkeypox) virus infection, according to results of a study published in The Journal of Infectious Diseases.
Researchers at the National Institute of Infectious Diseases in Japan performed this experimental study. A total of 132 approved drug candidates were screened in an mpox infection cell system using VerE6 cells. Drugs deemed to be potentially effective were evaluated further in cell viability, time-of-addition, and rescue assays.
The candidate drugs were of antiviral, antifungal, and antiparasitic/antiprotozoal classes, and the initial exposure tests were incubated for 72 hours. Tecovirimat and cidofovir — known mpox inhibitors — were used as positive controls.
At a concentration of 10 μM, 21 drugs were associated with at least a 20-fold increase in cell viability compared with dimethyl sulfoxide (DSMO) negative controls. Of these drugs, atovaquone, mefloquine, and molnupiravir were selected for secondary screening at concentrations of 3.3 μM.
In the secondary assay, all 3 of these drugs were significantly associated with reductions in mpox proteins at 24 hours following infection onset.
In dose-response experiments, the 3 drug candidates had superior anti-mpox potency than cidofovir (P ≤.05), indicated by lower 50% maximal virus inhibitory concentration (IC50) and 90% maximal virus inhibitory concentration (IC90) values. In addition, the combination of atovaquone plus tecovirimat was found to amplify antiviral activity without significant cytotoxicity.
To determine which stage of the viral life cycle that these drugs inhibited mpox, cells were treated at differing stages. Tecovirimat was bound to have antiviral activity throughout the whole life cycle and at the postentry/reinfection phase, whereas heparin was effective at the entry phase. For the candidate drugs, mefloquine had the best inhibition at the entry phase (P <.001), whereas inhibition for molnupiravir and atovaquone was best at the postentry/reinfection phase (both P ≤.005).
In electron microscopy assays, treatment with atovaquone and molnupiravir significantly reduced the number of infected cells, of which few were found to have virions despite the presence of cytoplasmic viral factories.
Using these findings and pharmacokinetic data, the researchers modeled the effect of these drugs in mpox-infected patients following the onset of rash. The model predicted that atovaquone would be the most effective in clinical settings, reducing the cumulative mpox viral load by 91.6% and the duration of seropositivity by 7.16 days.
The major limitation of this study was the lack of both animal model experiments and analysis among patients.
“Given the good tolerability profile of atovaquone in clinical settings, our present data provide attractive idea for supplementing atovaquone to improve the current approved anti-orthopoxvirus treatment,” the researchers concluded.
Akazawa D, Ohashi H, Hishiki T, et al. Potential anti-mpox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments. J Infect Dis. Publushed online March 9, 2023. doi:10.1093/infdis/jiad058