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Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells.
Sacramento, Carolina Q; Fintelman-Rodrigues, Natalia; Dias, Suelen S G; Temerozo, Jairo R; Da Silva, Aline de Paula D; da Silva, Carine S; Blanco, Camilla; Ferreira, André C; Mattos, Mayara; Soares, Vinicius C; Pereira-Dutra, Filipe; Miranda, Milene Dias; Barreto-Vieira, Debora F; da Silva, Marcos Alexandre N; Santos, Suzana S; Torres, Mateo; Chaves, Otávio Augusto; Rajoli, Rajith K R; Paccanaro, Alberto; Owen, Andrew; Bou-Habib, Dumith Chequer; Bozza, Patrícia T; Souza, Thiago Moreno L.
  • Sacramento CQ; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Fintelman-Rodrigues N; 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.
  • Dias SSG; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Temerozo JR; 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.
  • Da Silva APD; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • da Silva CS; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
  • Blanco C; Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
  • Ferreira AC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Mattos M; 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.
  • Soares VC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Pereira-Dutra F; 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.
  • Miranda MD; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Barreto-Vieira DF; 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.
  • da Silva MAN; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Santos SS; 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.
  • Torres M; Laboratório de Pesquisas Pré-Clínicas, Departamento de Ciências Biológicas, Universidade Iguaçu, Nova Iguaçu 26260-045, RJ, Brazil.
  • Chaves OA; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Rajoli RKR; 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.
  • Paccanaro A; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Owen A; Program of Immunology and Inflammation, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-617, RJ, Brazil.
  • Bou-Habib DC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil.
  • Bozza PT; Laboratório de Vírus Respiratório e do Sarampo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
  • Souza TML; Laboratório de Morfologia e Morfogênese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
Viruses ; 14(2)2022 02 11.
Article in English | MEDLINE | ID: covidwho-1687050
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Mefloquine / Chloroquine / Alveolar Epithelial Cells / SARS-CoV-2 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14020374

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Mefloquine / Chloroquine / Alveolar Epithelial Cells / SARS-CoV-2 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: V14020374