Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
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
_version_ 1785099375588933632
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
work_keys_str_mv AT akazawadaisuke potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT ohashihirofumi potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT hishikitakayuki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT moritatakeshi potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT iwanamishoya potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT kimkwangsu potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT jeongyongdam potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT parkeunsil potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT kataokamichiyo potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT shionoyakaho potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT mifunejunki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT tsuchimotokana potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT ojimashinjiro potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT azamaahaeruman potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT nakajimashogo potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT parkhyeongki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT yoshikawatomoki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT shimojimamasayuki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT kigakotaro potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT iwamishingo potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT maedaken potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT suzukitadaki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT ebiharahideki potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT takahashiyoshimasa potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments
AT watashikoichi potentialantimpoxvirusactivityofatovaquonemefloquineandmolnupiravirandtheirpotentialuseastreatments