Portal de Periódicos da CAPES

Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments

2023; Oxford University Press; Volume: 228; Issue: 5 Linguagem: Inglês

10.1093/infdis/jiad058

1537-6613

Daisuke Akazawa, Hirofumi Ohashi, Takayuki Hishiki, Takeshi Morita, Shoya Iwanami, Kwang Su Kim, Yong Dam Jeong, Eun‐Sil Park, Michiyo Kataoka, Kaho Shionoya, Junki Mifune, Kana Tsuchimoto, Shinjiro Ojima, Aa Haeruman Azam, Shogo Nakajima, Hyeongki Park, Tomoki Yoshikawa, Masayuki Shimojima, Kotaro Kiga, Shingo Iwami, Ken Maeda, Tadaki Suzuki, Hideki Ebihara, Yoshimasa Takahashi, Koichi Watashi,

Plant Virus Research Studies

Abstract Background Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling. Methods We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment. Results Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51–5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations. Conclusions These data suggest that atovaquone would be a potential candidate for treating mpox.