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, Sachiko; Park, Hyeongki; Yoshikawa, Tomoki; Shimojima, Masayuki; Kiga, Kotaro; Iwami, Shingo; Maeda, Ken; Suzuki, Tadaki; Ebihara, Hideki; Takahashi, Yoshimasa; Watashi, Koichi

doi:10.1093/infdis/jiad058

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…Proposed mechanisms for the antiviral effect of mefloquine against coronaviruses and other viruses such as Ebola and monkeypox virus include the inhibition of viral uptake by endocytosis and plasma membrane fusion and release of the viral genome from endosomes; however, a molecular basis for the mechanism is not reported (Akazawa et al, 2023;Sacramento et al, 2022;Shionoya et al, 2021). In fact, MFQ's effect on endocytosis has not been studied extensively in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Petcherski,

Tingley,

Martin

et al. 2023

Preprint

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SARS-CoV-2 can infect cells through endocytic uptake, a process which can be targeted by inhibition of lysosomal proteases. However, clinically this approach fared poorly with an oral regimen of hydroxychloroquine that was accompanied by significant toxicity due to off-target effects. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, 100-150 nm in diameter, and possess a negative surface charge which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2-WA1 and its Omicron variant in a human lung epithelium model. This study demonstrates that organelle-targeted delivery is an effective means to inhibit viral infection.

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Section: Discussionmentioning

confidence: 99%

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Petcherski,

Tingley,

Martin

et al. 2023

Preprint

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“…A recent screening of a library of approved drugs against MPXV in cytopathic effect assay identified atovaquone ( 145 ), mefloquine ( 146 ), and molnupiravir ( 147 ) as hits with IC 50 values of 0.52, 5.19, and 1.35 μM, respectively (Figure ). The IC 50 values for the positive controls tecovirimat ( 1 ) and cidofovir ( 3 ) were 2.80 nM and 13.7 μM, respectively. Drug time-of-addition experiment showed that mefloquine inhibited viral entry, while atovaquone and molnupiravir targeted postentry processes.…”

Section: Antivirals Against Orthopoxvirusesmentioning

confidence: 98%

“…Follow-up studies uncovered their antiviral activity against VACV and VARV (Figure 14). 169,170 Isatin-βthiosemicarbazone (IBT, 158) and marboran (159) inhibited CPXV (Brighton) and six VACV strains in cell culture. 171 Both compounds were highly effective in treating VACV-IHD virusinfected BALB/c mice when dosed by intraperitoneal injection at up to 72 h postinfection.…”

Section: Virucidal Compoundsmentioning

confidence: 99%

An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses

et al. 2023

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The current monkeypox outbreaks during the COVID-19 pandemic have reignited interest in orthopoxvirus antivirals. Monkeypox belongs to the Orthopoxvirus genus of the Poxviridae family, which also includes the variola virus, vaccinia virus, and cowpox virus. Two orally bioavailable drugs, tecovirimat and brincidofovir, have been approved for treating smallpox infections. Given their human safety profiles and in vivo antiviral efficacy in animal models, both drugs have also been recommended to treat monkeypox infection. To facilitate the development of additional orthopoxvirus antivirals, we summarize the antiviral activity, mechanism of action, and mechanism of resistance of orthopoxvirus antivirals. This perspective covers both direct-acting and host-targeting antivirals with an emphasis on drug candidates showing in vivo antiviral efficacy in animal models. We hope to speed the orthopoxvirus antiviral drug discovery by providing medicinal chemists with insights into prioritizing proper drug targets and hits for further development.

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“…An in vitro screen of 132 clinically approved drugs identified atovaquone, mefloquine, and molnupiravir with efficacy against MPXV. 52 Supportive and symptomatic care, which may be the only resources available for patients in resource-limited settings, play an important role in the management of monkeypox. Pain management is key and requires topical agents, oral medications, or nerve blocks.…”

Section: Managementmentioning

confidence: 99%

“…Thus, tecovirimat, brincidofovir, and cidofovir may be effective in the treatment and short-term prophylaxis of smallpox and related poxvirus infections in humans. An in vitro screen of 132 clinically approved drugs identified atovaquone, mefloquine, and molnupiravir with efficacy against MPXV …”

Section: Managementmentioning

confidence: 99%

Neurologic Complications of Smallpox and Monkeypox

et al. 2022

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ImportanceOrthopox viruses include smallpox virus, a once feared but now eradicated virus, as well as monkeypox virus. Monkeypox is an emerging virus initially isolated in 1958, previously unrecognized outside sub-Saharan Africa until a worldwide outbreak in May 2022. It is important to review known neurologic consequences of both these viruses, as complications of smallpox may be relevant to monkeypox, though complications of monkeypox may be rarer and perhaps less severe.ObservationsThis was a literature review of the known neurologic complications of smallpox, which include encephalitis, transverse myelitis, and acute disseminated encephalomyelitis among others; historical complications of smallpox vaccination, including postvaccinal encephalomyelitis; and the known neurologic complications of monkeypox, which include headaches and mood disturbances, as well as rare presentations of encephalitis, transverse myelitis, and seizures. Of concern is the possibility of viral persistence and systemic complications in immunocompromised individuals. Also provided were considerations for diagnosis, current treatment, and prevention of monkeypox.Conclusions and RelevanceMonkeypox should be considered in high-risk populations who present with neurologic syndromes. Diagnosis may require serology and polymerase chain reaction testing of blood and spinal fluid. Antiviral therapy should be initiated early in the course of the illness.

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

Cited by 10 publications

References 42 publications

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

Endo-Lysosome-Targeted Nanoparticle Delivery of Antiviral Therapy for Coronavirus Infections

An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses

Neurologic Complications of Smallpox and Monkeypox

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