Sacramento, Carolina Q, Fintelman-Rodrigues, Natalia, Dias, Suelen SG, Temerozo, Jairo R, Da Silva, Aline de Paula D, da Silva, Carine S, Blanco, Camilla, Ferreira, Andre C, Mattos, Mayara, Soares, Vinicius C et al (show 13 more authors)
(2022)
Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells.
VIRUSES-BASEL, 14 (2).
374-.
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | antimalarial drug, antiviral, COVID-19, mefloquine, SARS-CoV-2 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Jun 2022 09:51 |
| Last Modified: | 10 Feb 2023 05:54 |
| DOI: | 10.3390/v14020374 |
| Open Access URL: | https://doi.org/10.3390/v14020374 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3155991 |
Dimensions
Dimensions
