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Sustainable Development Goals
03 Saúde e Bem-EstarCollections
- IOC - Artigos de Periódicos [12982]
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UNLIKE CHLOROQUINE, MEFLOQUINE INHIBITS SARS-COV-2 INFECTION IN PHYSIOLOGICALLY RELEVANT CELLS
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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 M and EC90 of 5.3 M. It reduced SARS-CoV-2 RNA levels in monocytes and
prevented virus-induced enhancement of IL-6 and TNF- . 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.
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