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

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

doi:10.3390/v14020374

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 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.

Highlights

Repurposing of clinically approved drugs is considered a rapid way to respond to public health emergencies [1,2]
Mefloquine has emerged as a potential anti-SARS-CoV-2 drug through in vitro screening using Vero cells [19,21,52], its antiviral effect in physiologically relevant cellular systems on COVID-19 have not been studied
We found that two out of the six endocytosis-related pathways upregulated by mefloquine are downregulated by the infection (Table S5), suggesting that mefloquine can oppose the effect caused by SARS-CoV-2 infection

Summary

Introduction

Repurposing of clinically approved drugs is considered a rapid way to respond to public health emergencies [1,2]. The World Health Organization (WHO) and the University of Oxford launched Solidarity and Recovery clinical trials, respectively, against 2019 coronavirus disease (COVID-19) [3,4] just few months after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged [5]. WHO’s Solidarity trial failed to demonstrate a clinical benefit of chloroquine (CQ)/hydroxychloroquine (HCQ), lopinavir (LPV)/ritonavir (RTV) with or without interferon, and remdesivir (RDV) [6]. LPV/RTV and CQ/HCQ were not effective in the Recovery trial [7,8]. Independent clinical investigations of RDV demonstrated its clinical benefit when given early after the onset of illness [9,10,11]. Identification of host-acting agents, such as immunomodulatory drugs, has yielded several successful interventions at later stages of the disease, such as steroids and IL-6 antagonists [14]

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Results

Conclusion