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Unlike Chloroquine, mefloquine inhibits SARS-CoV-2 infection in physiologically relevant cells and does not induce viral variants

View ORCID ProfileCarolina Q. Sacramento, Natalia Fintelman-Rodrigues, Suelen S. G. Dias, Jairo R. Temerozo, Aline de Paula D. Da Silva, Carine S. da Silva, André C. Ferreira, Mayara Mattos, Vinicius C. Soares, Filipe Pereira-Dutra, Milene D. Miranda, Debora F. Barreto-Vieira, Marcos Alexandre N. da Silva, Suzana S. Santos, Mateo Torres, Rajith K R Rajoli, Alberto Paccanaro, Andrew Owen, Dumith Chequer Bou-Habib, Patrícia T. Bozza, Thiago Moreno L. Souza
doi: https://doi.org/10.1101/2021.07.21.451321
Carolina Q. Sacramento
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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  • ORCID record for Carolina Q. Sacramento
  • For correspondence: carol.qsacramento@gmail.com tmoreno@cdts.fiocruz.br
Natalia Fintelman-Rodrigues
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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Suelen S. G. Dias
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
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Jairo R. Temerozo
2National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
3Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
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Aline de Paula D. Da Silva
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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Carine S. da Silva
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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André C. Ferreira
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
4Universidade Iguaçu, Nova Iguaçu, RJ, Brazil
7National 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, RJ, Brazil
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Mayara Mattos
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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Vinicius C. Soares
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
5Program of Immunology and Inflammation, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
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Filipe Pereira-Dutra
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
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Milene D. Miranda
6Laboratório de Vírus Respiratório e do Sarampo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
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Debora F. Barreto-Vieira
8Laboratório de Morfologia e Morfogênese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
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Marcos Alexandre N. da Silva
8Laboratório de Morfologia e Morfogênese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
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Suzana S. Santos
9School of Applied Mathematics, Fundação Getulio Vargas, Rio de Janeiro, RJ, Brazil
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Mateo Torres
9School of Applied Mathematics, Fundação Getulio Vargas, Rio de Janeiro, RJ, Brazil
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Rajith K R Rajoli
10Centre of Excellence in Long acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
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Alberto Paccanaro
9School of Applied Mathematics, Fundação Getulio Vargas, Rio de Janeiro, RJ, Brazil
11Department of Computer Science, Royal Holloway, University of London, Egham, United Kingdom
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Andrew Owen
10Centre of Excellence in Long acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
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Dumith Chequer Bou-Habib
2National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
3Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil
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Patrícia T. Bozza
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
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Thiago Moreno L. Souza
1Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil
7National 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, RJ, Brazil
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  • For correspondence: carol.qsacramento@gmail.com tmoreno@cdts.fiocruz.br
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Abstract

Repositioning of clinical approved drugs could represent the fastest way to identify therapeutic options during public health emergencies, the majority of drugs explored for repurposing as antivirals for 2019 coronavirus disease (COVID-19) have failed to demonstrate clinical benefit. Without specific antivirals, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to cause major global mortality. Antimalarial drugs, such as chloroquine (CQ)/hydroxychloroquine (HCQ) and mefloquine have emerged as potential anti-SARS-CoV-2 antivirals. CQ/HCQ entered the Solidarity and RECOVERY clinical trials against COVID-19 and showed lack of efficacy. Importantly, mefloquine is not a 4-aminoquinoline like CQ and HCQ and has been previously repurposed for other respiratory diseases. Unlike the 4-aminoquinolines that accumulate in the high pH of intracellular lysosomes of the lung, the high respiratory tract penetration of mefloquine is driven by its high lipophilicity. While CQ and HCQ exhibit activity in Vero E6 cells, their activity is obviated in TMPRSS2-expressing cells, such as Calu-3 cells, which more accurately recapitulate in vivo entry mechanisms for SARS-CoV-2. Accordingly, here we report the anti-SARS-CoV-2 activity of mefloquine in Calu-3 type II pneumocytes and primary human monocytes. Mefloquine inhibited SARS-CoV-2 replication in Calu-3 cells with low cytotoxicity and EC50 and EC90 values of 1.2 and 5.3 µM, respectively. In addition, mefloquine reduced up to 68% the SARS-CoV-2 RNA levels in infected monocytes, reducing viral-induced inflammation. Mefloquine blocked early steps of the SARS-CoV-2 replicative cycle and was less prone than CQ to induce drug-associated viral mutations and synergized with RNA polymerase inhibitor. The pharmacological parameters of mefloquine are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points that this drug may accumulate in the lungs. These data indicate that mefloquine could represent an orally available clinically approved drug option against COVID-19 and should not be neglected on the basis of the failure of CQ and HCQ.

Competing Interest Statement

The authors have declared no competing interest.

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Unlike Chloroquine, mefloquine inhibits SARS-CoV-2 infection in physiologically relevant cells and does not induce viral variants
Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Suelen S. G. Dias, Jairo R. Temerozo, Aline de Paula D. Da Silva, Carine S. da Silva, André C. Ferreira, Mayara Mattos, Vinicius C. Soares, Filipe Pereira-Dutra, Milene D. Miranda, Debora F. Barreto-Vieira, Marcos Alexandre N. da Silva, Suzana S. Santos, Mateo Torres, Rajith K R Rajoli, Alberto Paccanaro, Andrew Owen, Dumith Chequer Bou-Habib, Patrícia T. Bozza, Thiago Moreno L. Souza
bioRxiv 2021.07.21.451321; doi: https://doi.org/10.1101/2021.07.21.451321
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Unlike Chloroquine, mefloquine inhibits SARS-CoV-2 infection in physiologically relevant cells and does not induce viral variants
Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Suelen S. G. Dias, Jairo R. Temerozo, Aline de Paula D. Da Silva, Carine S. da Silva, André C. Ferreira, Mayara Mattos, Vinicius C. Soares, Filipe Pereira-Dutra, Milene D. Miranda, Debora F. Barreto-Vieira, Marcos Alexandre N. da Silva, Suzana S. Santos, Mateo Torres, Rajith K R Rajoli, Alberto Paccanaro, Andrew Owen, Dumith Chequer Bou-Habib, Patrícia T. Bozza, Thiago Moreno L. Souza
bioRxiv 2021.07.21.451321; doi: https://doi.org/10.1101/2021.07.21.451321

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