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 50 of 1.2 µM and EC 90 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.
【저자키워드】 COVID-19, SARS-CoV-2, Antiviral, antimalarial drug, mefloquine, 【초록키워드】 Monocytes, therapy, Chloroquine, IL-6, Human, clinical trials, in vitro, anti-SARS-CoV-2, respiratory diseases, antimalarial, monocyte, Lungs, therapeutic, virus entry, pathway, plasma, SARS-CoV-2 RNA, HCQ, Calu-3 cell, information, mechanism of action, SARS-CoV-2 replication, Calu-3, TNF-α, Interaction, in vitro activity, Analysis, approved drug, differential expression, SARS-CoV-2 entry, clinical benefit, optimal dose, type II pneumocytes, cell line, parameter, solidarity, pharmacological, Cell, concentrations, Respiratory Coronavirus, TMPRSS2-expressing cells, predicted, lack, example, assays, investigated, clinically, inhibit, inhibited, reduced, prevented, accumulate, modulated, were assessed,