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Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells

2022; Multidisciplinary Digital Publishing Institute; Volume: 14; Issue: 2 Linguagem: Inglês

10.3390/v14020374

1999-4915

Carolina Q. Sacramento, Natália Fintelman-Rodrigues, Suelen da Silva Gomes Dias, Jairo R. Temerozo, Aline de Paula Dias da Silva, Carine S. da Silva, C. Fernández Blanco, André C. Ferreira, Mayara Mattos, Vinícius Cardoso Soares, Filipe S. Pereira‐Dutra, Milene Dias Miranda, Débora Ferreira Barreto-Vieira, Marcos Alexandre Nunes da Silva, Suzana de Siqueira Santos, Mateo Torres, Otávio Augusto Chaves, Rajith K. R. Rajoli, Alberto Paccanaro, Andrew Owen, Dumith Chequer Bou‐Habib, Patrı́cia T. Bozza, Thiago Moreno L. Souza,

Pharmacological Receptor Mechanisms and Effects

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.