학술논문
Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells.
Document Type
Article
Author
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
Source
Subject
*MEFLOQUINE
*ANTIMALARIALS
*COVID-19
*SARS-CoV-2
*CHLOROQUINE
*BIOLOGICAL assay
*CHEMICAL structure
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Language
ISSN
1999-4915
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. [ABSTRACT FROM AUTHOR]