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Sustainable Development Goals
03 Saúde e Bem-EstarCollections
- IOC - Preprint [153]
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UNLIKE CHLOROQUINE, MEFLOQUINE INHIBITS SARS-COV-2 INFECTION IN PHYSIOLOGICALLY RELEVANT CELLS AND DOES NOT INDUCE VIRAL VARIANTS
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Abstract
Repositioning of clinical approved drugs could represent the fastest way to identify
therapeutic options during public health emergencies, the majority of drugs explored for
repurposing as antivirals for 2019 coronavirus disease (COVID-19) have failed to
demonstrate clinical benefit. Without specific antivirals, the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to cause major global
mortality. Antimalarial drugs, such as chloroquine (CQ)/hydroxychloroquine (HCQ) and
mefloquine have emerged as potential anti-SARS-CoV-2 antivirals. CQ/HCQ entered the
Solidarity and RECOVERY clinical trials against COVID-19 and showed lack of efficacy.
Importantly, mefloquine is not a 4-aminoquinoline like CQ and HCQ and has been
previously repurposed for other respiratory diseases. Unlike the 4-aminoquinolines that
accumulate in the high pH of intracellular lysosomes of the lung, the high respiratory tract
penetration of mefloquine is driven by its high lipophilicity. While CQ and HCQ exhibit
activity in Vero E6 cells, their activity is obviated in TMPRSS2-expressing cells, such as
Calu-3 cells, which more accurately recapitulate in vivo entry mechanisms for SARS-CoV-
2. Accordingly, here we report the anti-SARS-CoV-2 activity of mefloquine in Calu-3 type
II pneumocytes and primary human monocytes. Mefloquine inhibited SARS-CoV-2
replication in Calu-3 cells with low cytotoxicity and EC50 and EC90 values of 1.2 and 5.3
μM, respectively. In addition, mefloquine reduced up to 68% the SARS-CoV-2 RNA levels
in infected monocytes, reducing viral-induced inflammation. Mefloquine blocked early
steps of the SARS-CoV-2 replicative cycle and was less prone than CQ to induce drugassociated
viral mutations and synergized with RNA polymerase inhibitor. The
pharmacological parameters of mefloquine are consistent with its plasma exposure in
humans and its tissue-to-plasma predicted coefficient points that this drug may accumulate
in the lungs. These data indicate that mefloquine could represent an orally available
clinically approved drug option against COVID-19 and should not be neglected on the basis
of the failure of CQ and HCQ.
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