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Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells

1
Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil
2
National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil
3
National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil
4
Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil
5
Laboratório de Pesquisas Pré-Clínicas, Departamento de Ciências Biológicas, Universidade Iguaçu, Nova Iguaçu 26260-045, RJ, Brazil
6
Program of Immunology and Inflammation, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-617, RJ, Brazil
7
Laboratório de Vírus Respiratório e do Sarampo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil
8
Laboratório de Morfologia e Morfogênese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil
9
School of Applied Mathematics, Fundação Getulio Vargas, Rio de Janeiro 22250-900, RJ, Brazil
10
Centre of Excellence in Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L1 8JX, UK
11
Department of Computer Science, Royal Holloway, University of London, Egham WC1E 7HU, UK
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Kin-Chow Chang and Leah Goulding
Viruses 2022, 14(2), 374; https://doi.org/10.3390/v14020374
Received: 29 November 2021 / Revised: 25 January 2022 / Accepted: 3 February 2022 / Published: 11 February 2022
(This article belongs to the Special Issue Towards Host-Centric Antivirals)
Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of clinically approved drugs could provide new information on the druggable steps of virus–host interaction. For example, chloroquine (CQ)/hydroxychloroquine (HCQ) lacks in vitro activity against SARS-CoV-2 in TMPRSS2-expressing cells, such as human pneumocyte cell line Calu-3, and likewise, failed to show clinical benefit in the Solidarity and Recovery clinical trials. Another antimalarial drug, mefloquine, which is not a 4-aminoquinoline like CQ/HCQ, has emerged as a potential anti-SARS-CoV-2 antiviral in vitro and has also been previously repurposed for respiratory diseases. Here, we investigated the anti-SARS-CoV-2 mechanism of action of mefloquine in cells relevant for the physiopathology of COVID-19, such as Calu-3 cells (that recapitulate type II pneumocytes) and monocytes. Molecular pathways modulated by mefloquine were assessed by differential expression analysis, and confirmed by biological assays. A PBPK model was developed to assess mefloquine’s optimal doses for achieving therapeutic concentrations. Mefloquine inhibited SARS-CoV-2 replication in Calu-3, with an EC50 of 1.2 µM and EC90 of 5.3 µM. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-α. Mefloquine reduced SARS-CoV-2 entry and synergized with Remdesivir. Mefloquine’s pharmacological parameters are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points suggesting that mefloquine may accumulate in the lungs. Altogether, our data indicate that mefloquine’s chemical structure could represent an orally available host-acting agent to inhibit virus entry. View Full-Text
Keywords: SARS-CoV-2; antiviral; COVID-19; antimalarial drug; mefloquine SARS-CoV-2; antiviral; COVID-19; antimalarial drug; mefloquine
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Figure 1

MDPI and ACS Style

Sacramento, C.Q.; Fintelman-Rodrigues, N.; Dias, S.S.G.; Temerozo, J.R.; Da Silva, A.d.P.D.; da Silva, C.S.; Blanco, C.; Ferreira, A.C.; Mattos, M.; Soares, V.C.; Pereira-Dutra, F.; Miranda, M.D.; Barreto-Vieira, D.F.; da Silva, M.A.N.; Santos, S.S.; Torres, M.; Chaves, O.A.; Rajoli, R.K.R.; Paccanaro, A.; Owen, A.; Bou-Habib, D.C.; Bozza, P.T.; Souza, T.M.L. Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells. Viruses 2022, 14, 374. https://doi.org/10.3390/v14020374

AMA Style

Sacramento CQ, Fintelman-Rodrigues N, Dias SSG, Temerozo JR, Da Silva AdPD, da Silva CS, Blanco C, Ferreira AC, Mattos M, Soares VC, Pereira-Dutra F, Miranda MD, Barreto-Vieira DF, da Silva MAN, Santos SS, Torres M, Chaves OA, Rajoli RKR, Paccanaro A, Owen A, Bou-Habib DC, Bozza PT, Souza TML. Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells. Viruses. 2022; 14(2):374. https://doi.org/10.3390/v14020374

Chicago/Turabian Style

Sacramento, Carolina Q., Natalia Fintelman-Rodrigues, Suelen S.G. Dias, Jairo R. Temerozo, Aline d.P.D. Da Silva, Carine S. da Silva, Camilla Blanco, André C. Ferreira, Mayara Mattos, Vinicius C. Soares, Filipe Pereira-Dutra, Milene D. Miranda, Debora F. Barreto-Vieira, Marcos A.N. da Silva, Suzana S. Santos, Mateo Torres, Otávio A. Chaves, Rajith K.R. Rajoli, Alberto Paccanaro, Andrew Owen, Dumith C. Bou-Habib, Patrícia T. Bozza, and Thiago M.L. Souza. 2022. "Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells" Viruses 14, no. 2: 374. https://doi.org/10.3390/v14020374

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