tetano
Editor, Senior Moderator
Viruses
. 2022 Feb 11;14(2):374.
doi: 10.3390/v14020374.
Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells
Carolina Q Sacramento[SUP] 1 2 [/SUP], Natalia Fintelman-Rodrigues[SUP] 1 2 [/SUP], Suelen S G Dias[SUP] 1 [/SUP], Jairo R Temerozo[SUP] 3 4 [/SUP], Aline de Paula D Da Silva[SUP] 1 2 [/SUP], Carine S da Silva[SUP] 1 2 [/SUP], Camilla Blanco[SUP] 1 2 [/SUP], André C Ferreira[SUP] 1 2 5 [/SUP], Mayara Mattos[SUP] 1 2 [/SUP], Vinicius C Soares[SUP] 1 6 [/SUP], Filipe Pereira-Dutra[SUP] 1 [/SUP], Milene Dias Miranda[SUP] 7 [/SUP], Debora F Barreto-Vieira[SUP] 8 [/SUP], Marcos Alexandre N da Silva[SUP] 8 [/SUP], Suzana S Santos[SUP] 9 [/SUP], Mateo Torres[SUP] 9 [/SUP], Otávio Augusto Chaves[SUP] 1 2 [/SUP], Rajith K R Rajoli[SUP] 10 [/SUP], Alberto Paccanaro[SUP] 9 11 [/SUP], Andrew Owen[SUP] 10 [/SUP], Dumith Chequer Bou-Habib[SUP] 3 4 [/SUP], Patrícia T Bozza[SUP] 1 [/SUP], Thiago Moreno L Souza[SUP] 1 2 [/SUP]
Affiliations
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 EC[SUB]50[/SUB] of 1.2 µM and EC[SUB]90[/SUB] 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.
Keywords: COVID-19; SARS-CoV-2; antimalarial drug; antiviral; mefloquine.
. 2022 Feb 11;14(2):374.
doi: 10.3390/v14020374.
Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells
Carolina Q Sacramento[SUP] 1 2 [/SUP], Natalia Fintelman-Rodrigues[SUP] 1 2 [/SUP], Suelen S G Dias[SUP] 1 [/SUP], Jairo R Temerozo[SUP] 3 4 [/SUP], Aline de Paula D Da Silva[SUP] 1 2 [/SUP], Carine S da Silva[SUP] 1 2 [/SUP], Camilla Blanco[SUP] 1 2 [/SUP], André C Ferreira[SUP] 1 2 5 [/SUP], Mayara Mattos[SUP] 1 2 [/SUP], Vinicius C Soares[SUP] 1 6 [/SUP], Filipe Pereira-Dutra[SUP] 1 [/SUP], Milene Dias Miranda[SUP] 7 [/SUP], Debora F Barreto-Vieira[SUP] 8 [/SUP], Marcos Alexandre N da Silva[SUP] 8 [/SUP], Suzana S Santos[SUP] 9 [/SUP], Mateo Torres[SUP] 9 [/SUP], Otávio Augusto Chaves[SUP] 1 2 [/SUP], Rajith K R Rajoli[SUP] 10 [/SUP], Alberto Paccanaro[SUP] 9 11 [/SUP], Andrew Owen[SUP] 10 [/SUP], Dumith Chequer Bou-Habib[SUP] 3 4 [/SUP], Patrícia T Bozza[SUP] 1 [/SUP], Thiago Moreno L Souza[SUP] 1 2 [/SUP]
Affiliations
- PMID: 35215969
- DOI: 10.3390/v14020374
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 EC[SUB]50[/SUB] of 1.2 µM and EC[SUB]90[/SUB] 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.
Keywords: COVID-19; SARS-CoV-2; antimalarial drug; antiviral; mefloquine.