Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments

Akazawa, D.; Ohashi, H.; Hishiki, T.; Morita, T.; Iwanami, S.; Kim, K. S.; Jeong, Y. D.; Park, E.-S.; Kataoka, M.; Shionoya, K.; Mifune, J.; Tsuchimoto, K.; Ojima, S.; Azam, A. H.; Nakajima, S.; Park, H.; Yoshikawa, T.; Shimojima, M.; Kiga, K.; Iwami, S.; Maeda, K.; Suzuki, T.; Ebihara, H.; Takahashi, Y.; Watashi, K.

doi:10.1101/2022.08.02.502485

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bioRxiv · 10.1101/2022.08.02.502485

Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments

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Abstract

Monkeypox virus (MPXV) is a zoonotic orthopoxvirus that causes smallpox-like symptoms in humans and caused an outbreak in May 2022 that led the WHO to declare global health emergency. In this study, from a screening of approved-drug libraries using an MPXV infection cell system, atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 M, which is more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process to impair intracellular virion accumulation. Inhibitors of dihydroorotate dehydrogenase, an atovaquones target enzyme, showed conserved anti-MPXV activities. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations. Moreover, atovaquone and molnupiravir exhibited pan-Orthopoxvirus activity against vaccinia and cowpox viruses. These data suggest that atovaquone would be potential candidates for treating monkeypox.

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Akazawa, D., Ohashi, H., Hishiki, T., Morita, T., Iwanami, S., Kim, K. S., Jeong, Y. D., Park, E.-S., Kataoka, M., Shionoya, K., Mifune, J., Tsuchimoto, K., Ojima, S., Azam, A. H., Nakajima, S., Park, H., Yoshikawa, T., Shimojima, M., Kiga, K., Iwami, S., Maeda, K., Suzuki, T., Ebihara, H., Takahashi, Y., Watashi, K.. 2022-08-02. Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments. https://doi.org/10.1101/2022.08.02.502485

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