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

Viruses

Rajith K. R. Rajoli¹  Andrew Owen¹  Suelen S. G. Dias²  Mayara Mattos²  Carine S. da Silva²  André C. Ferreira²  Vinicius C. Soares²  Filipe Pereira-Dutra²  Otávio Augusto Chaves²  Camilla Blanco²  Carolina Q. Sacramento²  Thiago Moreno L. Souza²  Patrícia T. Bozza²  Natalia Fintelman-Rodrigues²  Aline de Paula D. Da Silva²  Debora F. Barreto-Vieira³  Marcos Alexandre N. da Silva³  Milene Dias Miranda⁴  Jairo R. Temerozo⁵  Dumith Chequer Bou-Habib⁵  Mateo Torres⁶  Alberto Paccanaro⁶  Suzana S. Santos⁶ 

[1] Centre of Excellence in Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L1 8JX, UK;Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil;Laboratório de Morfologia e Morfogênese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil;Laboratório de Vírus Respiratório e do Sarampo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil;National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil;School of Applied Mathematics, Fundação Getulio Vargas, Rio de Janeiro 22250-900, RJ, Brazil;

关键词: SARS-CoV-2;    antiviral;    COVID-19;    antimalarial drug;    mefloquine;   

DOI  :  10.3390/v14020374

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown