{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:06:45Z","timestamp":1789578405066,"version":"build-2803163510"},"reference-count":70,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["COVID"],"award-info":[{"award-number":["COVID"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["COVID"],"award-info":[{"award-number":["COVID"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfeicoamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["COVID"],"award-info":[{"award-number":["COVID"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014555","name":"Fiotec","doi-asserted-by":"publisher","award":["COVID"],"award-info":[{"award-number":["COVID"]}],"id":[{"id":"10.13039\/501100014555","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Inova-Fiocruz","award":["COVID"],"award-info":[{"award-number":["COVID"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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\u2013host 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\u2019s optimal doses for achieving therapeutic concentrations. Mefloquine inhibited SARS-CoV-2 replication in Calu-3, with an EC50 of 1.2 \u00b5M and EC90 of 5.3 \u00b5M. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-\u03b1. Mefloquine reduced SARS-CoV-2 entry and synergized with Remdesivir. Mefloquine\u2019s 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\u2019s chemical structure could represent an orally available host-acting agent to inhibit virus entry.<\/jats:p>","DOI":"10.3390\/v14020374","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T20:35:28Z","timestamp":1644784528000},"page":"374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-7099","authenticated-orcid":false,"given":"Carolina Q.","family":"Sacramento","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2332-8338","authenticated-orcid":false,"given":"Natalia","family":"Fintelman-Rodrigues","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3104-0983","authenticated-orcid":false,"given":"Suelen S. G.","family":"Dias","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8092-2149","authenticated-orcid":false,"given":"Jairo R.","family":"Temerozo","sequence":"additional","affiliation":[{"name":"National Institute for Science and Technology on Neuroimmunomodulation (INCT\/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline de Paula D.","family":"Da Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine S.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Blanco","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 C.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Laborat\u00f3rio de Pesquisas Pr\u00e9-Cl\u00ednicas, Departamento de Ci\u00eancias Biol\u00f3gicas, Universidade Igua\u00e7u, Nova Igua\u00e7u 26260-045, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayara","family":"Mattos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0552-5995","authenticated-orcid":false,"given":"Vinicius C.","family":"Soares","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Program of Immunology and Inflammation, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-617, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1917-2876","authenticated-orcid":false,"given":"Filipe","family":"Pereira-Dutra","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-059X","authenticated-orcid":false,"given":"Milene Dias","family":"Miranda","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de V\u00edrus Respirat\u00f3rio e do Sarampo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-0755","authenticated-orcid":false,"given":"Debora F.","family":"Barreto-Vieira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Morfologia e Morfog\u00eanese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1707-6525","authenticated-orcid":false,"given":"Marcos Alexandre N.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Morfologia e Morfog\u00eanese Viral, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana S.","family":"Santos","sequence":"additional","affiliation":[{"name":"School of Applied Mathematics, Funda\u00e7\u00e3o Getulio Vargas, Rio de Janeiro 22250-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateo","family":"Torres","sequence":"additional","affiliation":[{"name":"School of Applied Mathematics, Funda\u00e7\u00e3o Getulio Vargas, Rio de Janeiro 22250-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-7659","authenticated-orcid":false,"given":"Ot\u00e1vio Augusto","family":"Chaves","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6015-5712","authenticated-orcid":false,"given":"Rajith K. R.","family":"Rajoli","sequence":"additional","affiliation":[{"name":"Centre of Excellence in Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L1 8JX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Paccanaro","sequence":"additional","affiliation":[{"name":"School of Applied Mathematics, Funda\u00e7\u00e3o Getulio Vargas, Rio de Janeiro 22250-900, RJ, Brazil"},{"name":"Department of Computer Science, Royal Holloway, University of London, Egham WC1E 7HU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-7651","authenticated-orcid":false,"given":"Andrew","family":"Owen","sequence":"additional","affiliation":[{"name":"Centre of Excellence in Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L1 8JX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-9045","authenticated-orcid":false,"given":"Dumith Chequer","family":"Bou-Habib","sequence":"additional","affiliation":[{"name":"National Institute for Science and Technology on Neuroimmunomodulation (INCT\/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8349-9529","authenticated-orcid":false,"given":"Patr\u00edcia T.","family":"Bozza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2212-3899","authenticated-orcid":false,"given":"Thiago Moreno L.","family":"Souza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Oswaldo Cruz Institute, Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/d41587-020-00003-1","article-title":"Coronavirus Puts Drug Repurposing on the Fast Track","volume":"38","author":"Harrison","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105969","DOI":"10.1016\/j.ijantimicag.2020.105969","article-title":"Drug Repositioning Is an Alternative for the Treatment of Coronavirus COVID-19","volume":"55","author":"Serafin","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_3","unstructured":"World Health Organization (2020). WHO R&D Blueprint: Informal Consultation on Prioritization of Candidate Therapeutic Agents for Use in Novel Coronavirus 2019 Infection, WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/d41573-021-00068-w","article-title":"RECOVERY 1 Year on: A Rare Success in the COVID-19 Clinical Trial Landscape","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","unstructured":"PubMed (2020, October 20). Identifying SARS-CoV-2-Related Coronaviruses in Malayan Pangolins, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/32218527\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2023184","article-title":"Repurposed Antiviral Drugs for COVID-19\u2014Interim WHO Solidarity Trial Results","volume":"384","author":"Pan","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"RECOVERY Collaborative Group (2020). Lopinavir-Ritonavir in Patients Admitted to Hospital with COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial. Lancet, 396, 1345\u20131352.","DOI":"10.1016\/S0140-6736(20)32013-4"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1056\/NEJMoa2022926","article-title":"Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19","volume":"383","author":"Horby","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1056\/NEJMoa2015301","article-title":"Remdesivir for 5 or 10 Days in Patients with Severe COVID-19","volume":"383","author":"Goldman","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of COVID-19\u2014Preliminary Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_12","unstructured":"(2021, November 22). Merck and Ridgeback\u2019s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study. Available online: https:\/\/www.merck.com\/news\/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat\/."},{"key":"ref_13","unstructured":"Pfizer (2021, November 29). Pfizer\u2019s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2\/3 EPIC-HR Study. Available online: https:\/\/www.pfizer.com\/news\/press-release\/press-release-detail\/pfizers-novel-covid-19-oral-antiviral-treatment-candidate."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.3389\/fimmu.2020.01844","article-title":"Immunomodulatory Drugs in the Management of SARS-CoV-2","volume":"11","author":"Burrage","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","unstructured":"Zimmer, C., Corum, J., and Wee, S.-L. (The New York Times, 2022). Coronavirus Vaccine Tracker, The New York Times."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An Interactive Web-Based Dashboard to Track COVID-19 in Real Time","volume":"20","author":"Dong","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_17","unstructured":"(2020, October 31). WHO Coronavirus Disease (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.12998\/wjcc.v8.i18.3920","article-title":"Special Features of SARS-CoV-2 in Daily Practice","volume":"8","author":"Charitos","year":"2020","journal-title":"World J. Clin. Cases"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e00819","DOI":"10.1128\/AAC.00819-20","article-title":"Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs","volume":"64","author":"Jeon","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/cpt.1909","article-title":"Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from Their Established Human Pharmacokinetics","volume":"108","author":"Arshad","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ellinger, B., Bojkova, D., Zaliani, A., Cinatl, J., Claussen, C., Westhaus, S., Reinshagen, J., Kuzikov, M., Wolf, M., and Geisslinger, G. (2020). Identification of Inhibitors of SARS-CoV-2 in-Vitro Cellular Toxicity in Human (Caco-2) Cells Using a Large Scale Drug Repurposing Collection. Res. Square.","DOI":"10.21203\/rs.3.rs-23951\/v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_23","unstructured":"PubMed (2021, June 17). Hypothesis for Potential Pathogenesis of SARS-CoV-2 Infection-a Review of Immune Changes in Patients with Viral Pneumonia, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/32196410\/."},{"key":"ref_24","first-page":"1","article-title":"Thromboinflammation in COVID-19: The Clot Thickens","volume":"bph.15594","author":"Iffah","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-019-0132-8","article-title":"Hydroxychloroquine, a Less Toxic Derivative of Chloroquine, Is Effective in Inhibiting SARS-CoV-2 Infection in Vitro","volume":"6","author":"Liu","year":"2020","journal-title":"Cell Discov."},{"key":"ref_26","unstructured":"(2021, June 17). Hydroxychloroquine-Mediated Inhibition of SARS-CoV-2 Entry Is Attenuated by TMPRSS2. Available online: https:\/\/journals.plos.org\/plospathogens\/article?id=10.1371\/journal.ppat.1009212."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"D\u2019Alessandro, S., Scaccabarozzi, D., Signorini, L., Perego, F., Ilboudo, D.P., Ferrante, P., and Delbue, S. (2020). The Use of Antimalarial Drugs against Viral Infection. Microorganisms, 8.","DOI":"10.3390\/microorganisms8010085"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1183\/13993003.00321-2015","article-title":"Mefloquine as a Potential Drug against Multidrug-Resistant Tuberculosis","volume":"46","author":"Krieger","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1128\/AAC.03036-14","article-title":"Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection","volume":"58","author":"Dyall","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","unstructured":"(2020, October 29). Prevention, C.-C. for D.C. and CDC-Malaria-Travelers-Recommendations for Immigrants from Malaria-Endemic Countries Planning to Return, Available online: https:\/\/www.cdc.gov\/malaria\/new_info\/2011\/mefloquine_pregnancy.html."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jff.2008.09.014","article-title":"A Modified Methylene Blue Assay for Accurate Cell Counting","volume":"1","author":"Felice","year":"2009","journal-title":"J. Funct. Foods"},{"key":"ref_32","unstructured":"(2020, October 20). CDC Information for Laboratories about Coronavirus (COVID-19), Available online: https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/lab\/rt-pcr-panel-primer-probes.html."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00825-20","DOI":"10.1128\/AAC.00825-20","article-title":"Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production","volume":"64","author":"Sacramento","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","unstructured":"Schatzmayr, H.G., Barth-Schatzmayr, O.M., and Barreto-Vieira, D.F. (2010). Modelo Animal Experimental para o Estudo da Patog\u00eanese dos V\u00edrus dengue Sorotipos 1 e 2. Manual de T\u00e9cnicas, Interci\u00eancia. [1st ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1590\/0074-02760150433","article-title":"Low Impact to Fixed Cell Processing Aiming Transmission Electron Microscopy","volume":"111","author":"Barth","year":"2016","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1083\/jcb.17.1.208","article-title":"The Use of Lead Citrate at High PH as an Electron-Opaque Stain in Electron Microscopy","volume":"17","author":"Reynolds","year":"1963","journal-title":"J. Cell Biol."},{"key":"ref_37","unstructured":"Nature Reviews Cancer (2021, March 10). The Connectivity Map: A New Tool for Biomedical Research. Available online: https:\/\/www.nature.com\/articles\/nrc2044."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI Gene Expression and Hybridization Array Data Repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102151","DOI":"10.1016\/j.isci.2021.102151","article-title":"Transcriptomic Profiling of SARS-CoV-2 Infected Human Cell Lines Identifies HSP90 as Target for COVID-19 Therapy","volume":"24","author":"Wyler","year":"2021","journal-title":"iScience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"EdgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"96ra77","DOI":"10.1126\/scitranslmed.3001318","article-title":"Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data","volume":"3","author":"Sirota","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1137\/141000671","article-title":"Julia: A Fresh Approach to Numerical Computing","volume":"59","author":"Bezanson","year":"2017","journal-title":"SIAM Rev."},{"key":"ref_46","first-page":"1","article-title":"Mean Body Weight, Height, Waist Circumference, and Body Mass Index Among Adults: United States, 1999\u20132000 through 2015\u20132016","volume":"122","author":"Fryar","year":"2018","journal-title":"Natl. Health Stat. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"751","DOI":"10.3109\/10408444.2012.709225","article-title":"An Improved Model to Predict Physiologically Based Model Parameters and Their Inter-Individual Variability from Anthropometry","volume":"42","author":"Bosgra","year":"2012","journal-title":"Crit. Rev. Toxicol"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Williams, L.R. (1994). Reference Values for Total Blood Volume and Cardiac Output in Humans, Oak Ridge National Lab.","DOI":"10.2172\/10186900"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/jps.20322","article-title":"Physiologically Based Pharmacokinetic Modeling 1: Predicting the Tissue Distribution of Moderate-to-Strong Bases","volume":"94","author":"Rodgers","year":"2005","journal-title":"J. Pharm. Sci"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0378-5173(99)00147-7","article-title":"A Compartmental Absorption and Transit Model for Estimating Oral Drug Absorption","volume":"186","author":"Yu","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2165\/00003088-200847040-00004","article-title":"Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Lineshape Analysis","volume":"47","author":"Peters","year":"2008","journal-title":"Clin. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e01218-20","DOI":"10.1128\/JVI.01218-20","article-title":"Broad Anti-Coronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo","volume":"94","author":"Weston","year":"2020","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/s41586-020-2575-3","article-title":"Chloroquine Does Not Inhibit Infection of Human Lung Cells with SARS-CoV-2","volume":"585","author":"Hoffmann","year":"2020","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Neerukonda, S.N., and Katneni, U. (2020). A Review on SARS-CoV-2 Virology, Pathophysiology, Animal Models, and Anti-Viral Interventions. Pathogens, 9.","DOI":"10.20944\/preprints202005.0204.v1"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Machhi, J., Herskovitz, J., Senan, A.M., Dutta, D., Nath, B., Oleynikov, M.D., Blomberg, W.R., Meigs, D.D., Hasan, M., and Patel, M. (2020). The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections. J. Neuroimmune Pharmacol., 1\u201328.","DOI":"10.1007\/s11481-020-09944-5"},{"key":"ref_56","unstructured":"BioRxiv (2020, October 22). The in Vitro Antiviral Activity of the Anti-Hepatitis C Virus (HCV) Drugs Daclatasvir and Sofosbuvir against SARS-CoV-2. Available online: https:\/\/www.biorxiv.org\/content\/10.1101\/2020.06.15.153411v2."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41420-021-00428-w","article-title":"SARS-CoV-2 Engages Inflammasome and Pyroptosis in Human Primary Monocytes","volume":"7","author":"Ferreira","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/S1473-3099(03)00806-5","article-title":"Effects of Chloroquine on Viral Infections: An Old Drug against Today\u2019s Diseases","volume":"3","author":"Savarino","year":"2003","journal-title":"Lancet Infect. Dis."},{"key":"ref_59","unstructured":"MedRxiv (2020, November 02). SARS-CoV-2 Induces Inflammasome-Dependent Pyroptosis and Downmodulation of HLA-DR in Human Monocytes. Available online: https:\/\/www.medrxiv.org\/content\/10.1101\/2020.08.25.20182055v2."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1182\/blood.2020007252","article-title":"Platelet Activation and Platelet-Monocyte Aggregate Formation Trigger Tissue Factor Expression in Patients with Severe COVID-19","volume":"136","author":"Hottz","year":"2020","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Rocco, P.R.M., Silva, P.L., Cruz, F.F., Junior, M.A.C.M., Tierno, P.F.G.M.M., Moura, M.A., Oliveira, L.F.G.D., Lima, C.C., Santos, E.A.D., and Junior, W.F. (2020). Early Use of Nitazoxanide in Mild COVID-19 Disease: Randomized, Placebo-Controlled Trial. medRxiv.","DOI":"10.1101\/2020.10.21.20217208"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"106214","DOI":"10.1016\/j.ijantimicag.2020.106214","article-title":"COVID-19 outpatients: Early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: A retrospective case series study","volume":"56","author":"Derwand","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3389\/fchem.2019.00365","article-title":"Molecular Orbital Insights of Transition Metal-Stabilized Carbocations","volume":"7","author":"Goodman","year":"2019","journal-title":"Front. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1128\/AAC.43.8.1870","article-title":"Mefloquine Is Active in Vitro and in Vivo against Mycobacterium Avium Complex","volume":"43","author":"Bermudez","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_65","unstructured":"(2020, November 08). Lariam Monograph for Professionals. Available online: https:\/\/www.drugs.com\/monograph\/lariam.html."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1128\/AAC.01187-09","article-title":"New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium Falciparum in Adults: A Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine","volume":"54","author":"Krudsood","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1365-2125.1994.tb04354.x","article-title":"The Pharmacokinetics of Chloroquine in Healthy Thai Subjects and Patients with Plasmodium Vivax Malaria","volume":"38","author":"Limpaibul","year":"1994","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_68","unstructured":"Therapeutics-Wiley Online Library (2021, June 16). Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development-Boffito-Clinical Pharmacology. Available online: https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2099."},{"key":"ref_69","unstructured":"Francisco, E.M. (2021, April 21). EMA Provides Recommendations on Compassionate Use of Remdesivir for COVID-19. Available online: https:\/\/www.ema.europa.eu\/en\/news\/ema-provides-recommendations-compassionate-use-remdesivir-covid-19."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1212\/01.WNL.0000095581.20961.7D","article-title":"Discovery of Nonxanthine Adenosine A2A Receptor Antagonists for the Treatment of Parkinson\u2019s Disease","volume":"61","author":"Weiss","year":"2003","journal-title":"Neurology"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/2\/374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:18:00Z","timestamp":1760134680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/2\/374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,11]]},"references-count":70,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["v14020374"],"URL":"https:\/\/doi.org\/10.3390\/v14020374","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.07.21.451321","asserted-by":"object"}]},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,11]]}}}