{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T17:57:28Z","timestamp":1764784648212,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["948\/19"],"award-info":[{"award-number":["948\/19"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Israel minstry of science","award":["66257"],"award-info":[{"award-number":["66257"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>SARS-CoV-2, the etiological agent of the COVID-19 pandemic, is a member of the Coronaviridae family. It is an enveloped virus with ion channels in its membrane, the most characterized of which is the E protein. Therefore, in an attempt to identify blockers of the E channel, we screened a library of 2839 approved-for-human-use drugs. Our approach yielded eight compounds that exhibited appreciable activity in three bacteria-based channel assays. Considering the fact that the E channel is the most conserved of all SARS-CoV-2 proteins, any inhibitor of its activity may provide an option to curb the viral spread. In addition, inhibitors can also enhance our ability to understand the exact role played by the E protein during the infectivity cycle. Finally, detailed electrophysiological analyses, alongside in vitro and in vivo studies will be needed to establish the exact potential of each of the blockers identified in our study.<\/jats:p>","DOI":"10.3390\/ph14070604","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T11:28:41Z","timestamp":1624447721000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Identification of SARS-CoV-2 E Channel Blockers from a Repurposed Drug Library"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5729-7066","authenticated-orcid":false,"given":"Prabhat Pratap Singh","family":"Tomar","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Krugliak","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-1746","authenticated-orcid":false,"given":"Isaiah T.","family":"Arkin","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. 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Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1056\/NEJMoa030781","article-title":"A novel coronavirus associated with severe acute respiratory syndrome","volume":"348","author":"Ksiazek","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1085952","article-title":"Characterization of a novel coronavirus associated with severe acute respiratory syndrome","volume":"300","author":"Rota","year":"2003","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0140-6736(20)30557-2","article-title":"SARS-CoV-2 is an appropriate name for the new coronavirus","volume":"395","author":"Wu","year":"2020","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12985-019-1182-0","article-title":"Coronavirus envelope protein: Current knowledge","volume":"16","author":"Schoeman","year":"2019","journal-title":"Virol. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1128\/JVI.01467-06","article-title":"A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo","volume":"81","author":"DeDiego","year":"2007","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6551","DOI":"10.1128\/JVI.00087-13","article-title":"Complete protection against severe acute respiratory syndrome coronavirus-mediated lethal respiratory disease in aged mice by immunization with a mouse-adapted virus lacking E protein","volume":"87","author":"Fett","year":"2013","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7721","DOI":"10.1128\/JVI.00304-08","article-title":"A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters","volume":"82","author":"Lamirande","year":"2008","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.virol.2010.01.004","article-title":"Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease","volume":"399","author":"Netland","year":"2010","journal-title":"Virology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1128\/JVI.03566-14","article-title":"Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates","volume":"89","author":"Fett","year":"2015","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/s41594-020-00536-8","article-title":"Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers","volume":"27","author":"Mandala","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.virol.2004.09.033","article-title":"SARS coronavirus E protein forms cation-selective ion channels","volume":"330","author":"Wilson","year":"2004","journal-title":"Virology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.virol.2006.05.028","article-title":"Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication","volume":"353","author":"Wilson","year":"2006","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.virusres.2015.02.023","article-title":"MERS coronavirus envelope protein has a single transmembrane domain that forms pentameric ion channels","volume":"201","author":"Surya","year":"2015","journal-title":"Virus Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bbrc.2020.05.206","article-title":"SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine","volume":"530","author":"Arkin","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zheng, J., and Trudeau, M.C. (2015). Handbook of Ion Channels, CRC Press.","DOI":"10.1201\/b18027"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1099\/vir.0.000201","article-title":"Viroporins: Structure, function and potential as antiviral targets","volume":"96","author":"Scott","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.2174\/0929867323666160210124930","article-title":"Fight Against H1N1 Influenza A Virus: Recent Insights Towards the Development of Druggable Compounds","volume":"23","author":"Tonelli","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1126\/science.144.3620.862","article-title":"Antiviral activity of 1-adamantanamine (amantadine)","volume":"144","author":"Davies","year":"1964","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1002\/j.1460-2075.1985.tb04038.x","article-title":"The molecular basis of the specific anti-influenza action of amantadine","volume":"4","author":"Hay","year":"1985","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0092-8674(92)90452-I","article-title":"Influenza Virus M2 Protein Has Ion Channel Activity","volume":"69","author":"Pinto","year":"1992","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/S0140-6736(05)67340-0","article-title":"Resistance to anti-influenza agents","volume":"366","author":"Guan","year":"2005","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1016\/j.jmb.2016.08.007","article-title":"Mapping the Resistance Potential of Influenza\u2019s H+ Channel against an Antiviral Blocker","volume":"428","author":"Assa","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.bbamem.2010.08.021","article-title":"Quantitative analysis of influenza M2 channel blockers","volume":"1808","author":"Astrahan","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Taube, R., Alhadeff, R., Assa, D., Krugliak, M., and Arkin, I.T. (2014). Bacteria-based analysis of HIV-1 Vpu channel activity. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105387"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tomar, P.P.S., Oren, R., Krugliak, M., and Arkin, I.T. (2019). Potential Viroporin Candidates From Pathogenic Viruses Using Bacteria-Based Bioassays. Viruses, 11.","DOI":"10.3390\/v11070632"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tomar, P.P.S., Krugliak, M., and Arkin, I.T. (2021). Blockers of the SARS-CoV-2 3a Channel Identified by Targeted Drug Repurposing. Viruses, 13.","DOI":"10.3390\/v13030532"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.bbamem.2013.07.033","article-title":"Computational and experimental analysis of drug binding to the Influenza M2 channel","volume":"1838","author":"Alhadeff","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s002030050425","article-title":"Requirement of a Large K+-Uptake Capacity and of Extracytoplasmic Protease Activity for Protamine Resistance of Escherichia Coli","volume":"167","author":"Stumpe","year":"1997","journal-title":"Arch. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/28190","article-title":"Visualizing Secretion and Synaptic Transmission With pH-Sensitive Green Fluorescent Proteins","volume":"394","author":"Rothman","year":"1998","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.1021\/acs.biochem.8b00721","article-title":"A Robust Proton Flux (pHlux) Assay for Studying the Function and Inhibition of the Influenza A M2 Proton Channel","volume":"57","author":"Santner","year":"2018","journal-title":"Biochemistry"},{"key":"ref_34","first-page":"997","article-title":"Tetrodotoxin, saxitoxin and their significance in the study of excitation phenomena","volume":"18","author":"Kao","year":"1966","journal-title":"Pharmacol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/311538a0","article-title":"Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists","volume":"311","author":"Hess","year":"1984","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12329","DOI":"10.1073\/pnas.210244497","article-title":"A structural basis for drug-induced long QT syndrome","volume":"97","author":"Mitcheson","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/0165-6147(92)90079-L","article-title":"Receptor sites for Ca2+ channel antagonists","volume":"13","author":"Catterall","year":"1992","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1073\/pnas.82.20.7096","article-title":"3\u2019-Azido-3\u2019-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III\/lymphadenopathy-associated virus in vitro","volume":"82","author":"Mitsuya","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1056\/NEJM198707233170401","article-title":"The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial","volume":"317","author":"Fischl","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1021\/jo01030a546","article-title":"Nucleosides. V. The Monomesylates of 1-(2\u2019-Deoxy-\u03b2-D-lyxofuranosyl)thymine1,2","volume":"29","author":"Horwitz","year":"1964","journal-title":"J. Org. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic options for the 2019 novel coronavirus (2019-nCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of Covid-19-Final Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"m4457","DOI":"10.1136\/bmj.m4457","article-title":"Covid-19: What now for remdesivir?","volume":"371","author":"Hsu","year":"2020","journal-title":"BMJ"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"WHO Solidarity Trial Consortium, Pan, H., Peto, R., Henao-Restrepo, A.M., Preziosi, M.P., Sathiyamoorthy, V., Abdool Karim, Q., Alejandria, M.M., Hern\u00e1ndez Garc\u00eda, C., and Kieny, M.P. (2020). Repurposed Antiviral Drugs for Covid-19-Interim WHO Solidarity Trial Results. N. Engl. J. Med.","DOI":"10.1101\/2020.10.15.20209817"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41586-020-2577-1","article-title":"Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing","volume":"586","author":"Riva","year":"2020","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5957","DOI":"10.1021\/acs.biochem.8b00722","article-title":"Random Mutagenesis Analysis of the Influenza A M2 Proton Channel Reveals Novel Resistance Mutants","volume":"57","author":"Santner","year":"2018","journal-title":"Biochemistry"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/7\/604\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:53Z","timestamp":1760163713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/7\/604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,23]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ph14070604"],"URL":"https:\/\/doi.org\/10.3390\/ph14070604","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2021,6,23]]}}}