期刊
VIRUSES-BASEL
卷 14, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/v14020374
关键词
SARS-CoV-2; antiviral; COVID-19; antimalarial drug; mefloquine
类别
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [441019/2020-0, 307162/2017-6]
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/210.182/2020, E-26/201.067/2021, E-26/210.112/2020]
- CNPq
- CAPES
- FAPERJ through the National Institutes of Science and Technology Program (INCT) on Diseases of Neglected Populations (INCT-IDPN) [465313/2014-0]
- FAPERJ through the National Institutes of Science and Technology Program (INCT) on Neuroimmunomodulation (INCT-NIM) [443217/2015-1]
- Oswaldo Cruz Foundation/FIOCRUZ under Inova Program (B3-Bovespa funding) [VGPDI-032-ARVC-20, 48400295262517]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
- Mercosur Structural Convergence Fund (FOCEM, Mercosur) [03/11]
- EPSRC [EP/R024804/1]
Despite the lack of in vitro activity, chloroquine has shown potential in inhibiting SARS-CoV-2 replication and reducing virus-induced inflammation. It can also reduce virus entry and synergize with remdesivir.
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 mu M and EC90 of 5.3 mu M. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-alpha. 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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