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Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments
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 d...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469127/ https://www.ncbi.nlm.nih.gov/pubmed/36892247 http://dx.doi.org/10.1093/infdis/jiad058 |
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author | Akazawa, Daisuke Ohashi, Hirofumi Hishiki, Takayuki Morita, Takeshi Iwanami, Shoya Kim, Kwang Su Jeong, Yong Dam Park, Eun-Sil Kataoka, Michiyo Shionoya, Kaho Mifune, Junki Tsuchimoto, Kana Ojima, Shinjiro Azam, Aa Haeruman Nakajima, Shogo Park, Hyeongki Yoshikawa, Tomoki Shimojima, Masayuki Kiga, Kotaro Iwami, Shingo Maeda, Ken Suzuki, Tadaki Ebihara, Hideki Takahashi, Yoshimasa Watashi, Koichi |
author_facet | Akazawa, Daisuke Ohashi, Hirofumi Hishiki, Takayuki Morita, Takeshi Iwanami, Shoya Kim, Kwang Su Jeong, Yong Dam Park, Eun-Sil Kataoka, Michiyo Shionoya, Kaho Mifune, Junki Tsuchimoto, Kana Ojima, Shinjiro Azam, Aa Haeruman Nakajima, Shogo Park, Hyeongki Yoshikawa, Tomoki Shimojima, Masayuki Kiga, Kotaro Iwami, Shingo Maeda, Ken Suzuki, Tadaki Ebihara, Hideki Takahashi, Yoshimasa Watashi, Koichi |
author_sort | Akazawa, Daisuke |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10469127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104691272023-09-01 Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments Akazawa, Daisuke Ohashi, Hirofumi Hishiki, Takayuki Morita, Takeshi Iwanami, Shoya Kim, Kwang Su Jeong, Yong Dam Park, Eun-Sil Kataoka, Michiyo Shionoya, Kaho Mifune, Junki Tsuchimoto, Kana Ojima, Shinjiro Azam, Aa Haeruman Nakajima, Shogo Park, Hyeongki Yoshikawa, Tomoki Shimojima, Masayuki Kiga, Kotaro Iwami, Shingo Maeda, Ken Suzuki, Tadaki Ebihara, Hideki Takahashi, Yoshimasa Watashi, Koichi J Infect Dis Major Article 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. Oxford University Press 2023-03-09 /pmc/articles/PMC10469127/ /pubmed/36892247 http://dx.doi.org/10.1093/infdis/jiad058 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Major Article Akazawa, Daisuke Ohashi, Hirofumi Hishiki, Takayuki Morita, Takeshi Iwanami, Shoya Kim, Kwang Su Jeong, Yong Dam Park, Eun-Sil Kataoka, Michiyo Shionoya, Kaho Mifune, Junki Tsuchimoto, Kana Ojima, Shinjiro Azam, Aa Haeruman Nakajima, Shogo Park, Hyeongki Yoshikawa, Tomoki Shimojima, Masayuki Kiga, Kotaro Iwami, Shingo Maeda, Ken Suzuki, Tadaki Ebihara, Hideki Takahashi, Yoshimasa Watashi, Koichi Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title | Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title_full | Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title_fullStr | Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title_full_unstemmed | Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title_short | Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments |
title_sort | potential anti-mpox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments |
topic | Major Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469127/ https://www.ncbi.nlm.nih.gov/pubmed/36892247 http://dx.doi.org/10.1093/infdis/jiad058 |
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