{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:08:32Z","timestamp":1785766112548,"version":"3.56.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019ZDLSF02-04 82072268 81871649 2016YFC1202903"],"award-info":[{"award-number":["2019ZDLSF02-04 82072268 81871649 2016YFC1202903"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Hantaviruses, the causative agent for two types of hemorrhagic fevers, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are distributed from Eurasia to America. HFRS and HPS have mortality rates of up to 15% or 45%, respectively. Currently, no certified therapeutic has been licensed to treat hantavirus infection. In this study, we discovered that benidipine hydrochloride, a calcium channel blocker, inhibits the entry of hantaviruses <jats:italic>in vitro<\/jats:italic>. Moreover, an array of calcium channel inhibitors, such as cilnidipine, felodipine, amlodipine, manidipine, nicardipine, and nisoldipine, exhibit similar antiviral properties. Using pseudotyped vesicular stomatitis viruses harboring the different hantavirus glycoproteins, we demonstrate that benidipine hydrochloride inhibits the infection by both HFRS- and HPS-causing hantaviruses. The results of our study indicate the possibility of repurposing FDA-approved calcium channel blockers for the treatment of hantavirus infection, and they also indicate the need for further research <jats:italic>in vivo<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fphar.2022.940178","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T07:12:56Z","timestamp":1661757176000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Dihydropyridine-derived calcium channel blocker as a promising anti-hantavirus entry inhibitor"],"prefix":"10.3389","volume":"13","author":[{"given":"Bin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuewu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangchao","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Airong","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikai","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingfeng","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanglin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.molcel.2017.05.028","article-title":"Intracellular Ca(2+) sensing: Its role in calcium homeostasis and signaling","volume":"66","author":"Bagur","year":"2017","journal-title":"Mol. Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.chom.2016.07.004","article-title":"A screen of FDA-approved drugs for inhibitors of Zika virus infection","volume":"20","author":"Barrows","year":"2016","journal-title":"Cell Host Microbe"},{"key":"B3","doi-asserted-by":"publisher","first-page":"E610","DOI":"10.3390\/v11070610","article-title":"Progress on the prevention and treatment of hantavirus disease","volume":"11","author":"Brocato","year":"2019","journal-title":"Viruses"},{"key":"B4","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3389\/fcimb.2016.00185","article-title":"Incorporation of GM-CSF or CD40L enhances the immunogenicity of hantaan virus-like particles","volume":"6","author":"Cheng","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.3390\/v6041801","article-title":"Hantavirus Gn and Gc envelope glycoproteins: key structural units for virus cell entry and virus assembly","volume":"6","author":"Cifuentes-Munoz","year":"2014","journal-title":"Viruses"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S588","DOI":"10.1093\/infdis\/jiy332","article-title":"The calcium channel blocker bepridil demonstrates efficacy in the murine model of marburg virus disease","volume":"218","author":"DeWald","year":"2018","journal-title":"J. Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.coviro.2021.07.009","article-title":"The surface glycoproteins of hantaviruses","volume":"50","author":"Guardado-Calvo","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1007\/s12250-016-3899-x","article-title":"Hantavirus infection: a global zoonotic challenge","volume":"32","author":"Jiang","year":"2017","journal-title":"Virol. Sin."},{"key":"B9","doi-asserted-by":"publisher","first-page":"290ra89","DOI":"10.1126\/scitranslmed.aaa5597","article-title":"A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity","volume":"7","author":"Johansen","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1128\/CMR.00062-09","article-title":"A global perspective on hantavirus ecology, epidemiology, and disease","volume":"23","author":"Jonsson","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"E775","DOI":"10.3390\/pathogens9090775","article-title":"Orthohantaviruses, emerging zoonotic pathogens","volume":"9","author":"Kabwe","year":"2020","journal-title":"Pathogens"},{"key":"B12","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1254\/jjp.52.553","article-title":"Protection by benidipine hydrochloride (KW-3049), a calcium antagonist, of ischemic kidney in rats via inhibitions of Ca-overload, ATP-decline and lipid peroxidation","volume":"52","author":"Karasawa","year":"1990","journal-title":"Jpn. J. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"204ra131","DOI":"10.1126\/scitranslmed.3006827","article-title":"siRNA screen for genes that affect Jun\u00edn virus entry uncovers voltage-gated calcium channels as a therapeutic target","volume":"5","author":"Lavanya","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/s41422-019-0214-z","article-title":"Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality","volume":"29","author":"Li","year":"2019","journal-title":"Cell Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.atherosclerosis.2004.08.020","article-title":"Benidipine, a dihydropyridine-calcium channel blocker, prevents lysophosphatidylcholine-induced injury and reactive oxygen species production in human aortic endothelial cells","volume":"178","author":"Matsubara","year":"2005","journal-title":"Atherosclerosis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"685","DOI":"10.3390\/v13040685","article-title":"Identification of novel antiviral compounds targeting entry of hantaviruses","volume":"13","author":"Mayor","year":"2021","journal-title":"Viruses"},{"key":"B17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/bs.aivir.2019.07.002","article-title":"Hantavirus entry: Perspectives and recent advances","volume":"104","author":"Mittler","year":"2019","journal-title":"Adv. Virus Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/1440-1681.13403","article-title":"Hantavirus diseases pathophysiology, their diagnostic strategies and therapeutic approaches: A review","volume":"48","author":"Munir","year":"2020","journal-title":"Clin. Exp. Pharmacol. physiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3389\/fcimb.2020.00399","article-title":"Orthohantavirus pathogenesis and cell tropism","volume":"10","author":"Noack","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","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":"B21","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1126\/science.1258758","article-title":"Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment","volume":"347","author":"Sakurai","year":"2015","journal-title":"Sci. (New York, N.Y.)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"E705","DOI":"10.3390\/v12070705","article-title":"Repurposing therapeutics for potential treatment of SARS-CoV-2: A review","volume":"12","author":"Santos","year":"2020","journal-title":"Viruses"},{"key":"B23","doi-asserted-by":"publisher","first-page":"8721","DOI":"10.1128\/JVI.00144-10","article-title":"Virus-induced Ca2+ influx extends survival of west nile virus-infected cells","volume":"84","author":"Scherbik","year":"2010","journal-title":"J. Virol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2020.08.023","article-title":"The hantavirus surface glycoprotein lattice and its fusion control mechanism","volume":"183","author":"Serris","year":"2020","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.3389\/fmicb.2018.02954","article-title":"Annexin A2 in virus infection","volume":"9","author":"Taylor","year":"2018","journal-title":"Front. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/nrmicro3066","article-title":"Uncovering the mysteries of hantavirus infections","volume":"11","author":"Vaheri","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1111\/j.1476-5381.1990.tb14074.x","article-title":"Mechanisms of long-lasting effects of benidipine on Ca current in guinea-pig ventricular cells","volume":"100","author":"Yamamoto","year":"1990","journal-title":"Br. J. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1254\/jphs.dtj05001x","article-title":"Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker","volume":"100","author":"Yao","year":"2006","journal-title":"J. Pharmacol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1211\/0022357001774200","article-title":"Benidipine inhibits apoptosis during ischaemic acute renal failure in rats","volume":"52","author":"Yao","year":"2000","journal-title":"J. Pharm. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.bbrc.2020.04.088","article-title":"N6-methyladenosine modifications enhance enterovirus 71 ORF translation through METTL3 cytoplasmic distribution","volume":"527","author":"Yao","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.3389\/fphar.2019.01203","article-title":"An improved enzyme-linked focus formation assay revealed baloxavir acid as a potential antiviral therapeutic against hantavirus infection","volume":"10","author":"Ye","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.meegid.2014.11.009","article-title":"Hantaan virus can infect human keratinocytes and activate an interferon response through the nuclear translocation of IRF-3","volume":"29","author":"Ye","year":"2015","journal-title":"Infect. Genet. Evol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.3389\/fmicb.2020.01105","article-title":"Remdesivir (GS-5734) impedes enterovirus replication through viral RNA Synthesis inhibition","volume":"11","author":"Ye","year":"2020","journal-title":"Front. Microbiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discov."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.940178\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T07:12:58Z","timestamp":1661757178000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.940178\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,29]]},"references-count":34,"alternative-id":["10.3389\/fphar.2022.940178"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.940178","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,29]]},"article-number":"940178"}}