{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:15:14Z","timestamp":1787030114500,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israeli Science Foundation"},{"name":"Israeli Science Ministry"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Flavivirus infections, such as those caused by dengue and West Nile viruses, emerge as new challenges for the global healthcare sector. It has been found that these two viruses encode ion channels collectively termed viroporins. Therefore, drug molecules that block such ion-channel activity can serve as potential antiviral agents and may play a primary role in therapeutic purposes. We screened 2839 FDA-approved drugs and compounds in advanced experimental phases using three bacteria-based channel assays to identify such ion channel blockers. We primarily followed a negative genetic screen in which the channel is harmful to the bacteria due to excessive membrane permeabilization that can be relieved by a blocker. Subsequently, we cross-checked the outcome with a positive genetic screen and a pH-dependent assay. The following drugs exhibited potential blocker activities: plerixafor, streptomycin, tranexamic acid, CI-1040, glecaprevir, kasugamycin, and mesna were effective against dengue virus DP1. In contrast, idasanutlin, benzbromarone, 5-azacytidine, and plerixafor were effective against West Nile Virus MgM. These drugs can serve as future antiviral therapeutic agents following subsequent in vitro and in vivo efficacy studies.<\/jats:p>","DOI":"10.3390\/v14081750","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T01:51:11Z","timestamp":1660269071000},"page":"1750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Searching for Blockers of Dengue and West Nile Virus Viroporins"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5121-2626","authenticated-orcid":false,"given":"Hiya","family":"Lahiri","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 9190400, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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. Safra Campus, Jerusalem 9190400, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"ref_1","unstructured":"GBD 2017 Causes of Death Collaborators (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980\u20132017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 392, 1736\u20131788."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_3","unstructured":"Knipe, D.M., and Howley, P.M. (2013). Fields Virology, Wolters Kluwer\/Lippincott Williams & Wilkins Health. [6th ed.]."},{"key":"ref_4","unstructured":"Centers for Disease Control and Prevention (2020). West Nile Virus Disease Cases and Deaths Reported to CDC by Year and Clinical Presentation, 1999\u20132020."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2101","DOI":"10.1002\/rmv.2101","article-title":"Dengue: Status of current and under-development vaccines","volume":"30","author":"Redoni","year":"2020","journal-title":"Rev. Med. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1021\/acsmedchemlett.1c00617","article-title":"Antivirals against (Re)emerging Flaviviruses: Should We Target the Virus or the Host?","volume":"13","author":"Saiz","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1126\/science.4023707","article-title":"Nucleotide sequence of yellow fever virus: Implications for flavivirus gene expression and evolution","volume":"229","author":"Rice","year":"1985","journal-title":"Science"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrmicro2820","article-title":"Viroporins: Structure and biological functions","volume":"10","author":"Nieva","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0014-5793(03)00780-4","article-title":"Viroporins","volume":"552","author":"Gonzalez","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_11","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_12","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_13","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_14","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_15","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_16","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_17","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_18","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_19","doi-asserted-by":"crossref","unstructured":"Tomar, P.P.S., Krugliak, M., and Arkin, I.T. (2021). Identification of SARS-CoV-2 E Channel Blockers from a Repurposed Drug Library. Pharmaceuticals, 14.","DOI":"10.3390\/ph14070604"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tomar, P.P.S., Krugliak, M., Singh, A., and Arkin, I.T. (2022). Zika M-A Potential Viroporin: Mutational Study and Drug Repurposing. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030641"},{"key":"ref_21","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_22","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_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0021-9258(18)86000-8","article-title":"A buffer solution for colorimetric comparison","volume":"49","author":"McIlvaine","year":"1921","journal-title":"J. Biol. Chem."},{"key":"ref_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.virusres.2019.02.011","article-title":"Drug repurposing for new, efficient, broad spectrum antivirals","volume":"264","author":"Risco","year":"2019","journal-title":"Virus Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wong, R.W., Balachandran, A., Ostrowski, M.A., and Cochrane, A. (2013). Digoxin suppresses HIV-1 replication by altering viral RNA processing. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003241"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.antiviral.2008.01.156","article-title":"Anti-HSV activity of digitoxin and its possible mechanisms","volume":"79","author":"Su","year":"2008","journal-title":"Antivir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16200","DOI":"10.1038\/s41598-020-72879-7","article-title":"Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19","volume":"10","author":"Cho","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Singh, A., and Arkin, I.T. (2022). Targeting Viral Ion Channels: A Promising Strategy to Curb SARS-CoV-2. Pharmaceuticals, 15.","DOI":"10.3390\/ph15040396"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1750\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:07:03Z","timestamp":1760141223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["v14081750"],"URL":"https:\/\/doi.org\/10.3390\/v14081750","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]}}}