{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:45:50Z","timestamp":1784771150290,"version":"3.55.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["2019ACCP-MS03"],"award-info":[{"award-number":["2019ACCP-MS03"]}],"id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    Lujo virus (LUJV) belongs to the Old World (OW) genus\n                    <jats:italic>Mammarenavirus<\/jats:italic>\n                    (family Arenaviridae). It is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane (TM) domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2021.793519","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T07:16:27Z","timestamp":1638429387000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library"],"prefix":"10.3389","volume":"12","author":[{"given":"Junyuan","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxia","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengfu","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e1000455","DOI":"10.1371\/journal.ppat.1000455","article-title":"Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa","volume":"5","author":"Briese","year":"2009","journal-title":"PLoS Pathog."},{"key":"ref2","volume-title":"Fields Virology.","author":"Buchmeier","year":"2007"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s12250-020-00286-3","article-title":"Characterizing the Lassa virus envelope glycoprotein membrane proximal external region for its role in Fusogenicity","volume":"36","author":"Cao","year":"2021","journal-title":"Virol. Sin."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"94","DOI":"10.3390\/cells9010094","article-title":"Host calcium channels and pumps in viral infections","volume":"9","author":"Chen","year":"2019","journal-title":"Cell"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1038\/s41564-018-0224-5","article-title":"Structural basis for receptor recognition by Lujo virus","volume":"3","author":"Cohen-Dvashi","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/s0014-5793(03)00160-1","article-title":"Signal peptide of Lassa virus glycoprotein GP-C exhibits an unusual length","volume":"538","author":"Eichler","year":"2003","journal-title":"FEBS Lett."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"5458","DOI":"10.1128\/JVI.78.10.5458-5465.2004","article-title":"Properties of replication-competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses","volume":"78","author":"Garbutt","year":"2004","journal-title":"J. Virol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1111\/cas.13234","article-title":"BRAF mutations are associated with increased iron regulatory protein-2 expression in colorectal tumorigenesis","volume":"108","author":"Horniblow","year":"2017","journal-title":"Cancer Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"19967","DOI":"10.1073\/pnas.1108910108","article-title":"X-ray structure of the arenavirus glycoprotein GP2 in its postfusion hairpin conformation","volume":"108","author":"Igonet","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1128\/JVI.75.3.1576-1580.2001","article-title":"Ebola virus glycoprotein: proteolytic processing, acylation, cell tropism, and detection of neutralizing antibodies","volume":"75","author":"Ito","year":"2001","journal-title":"J. Virol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1128\/AAC.03659-14","article-title":"Antiviral potential of ERK\/MAPK and PI3K\/AKT\/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis","volume":"59","author":"Kindrachuk","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3023","DOI":"10.1007\/s00705-020-04731-2","article-title":"2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales","volume":"165","author":"Kuhn","year":"2020","journal-title":"Arch. Virol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"10768","DOI":"10.1128\/JVI.00941-08","article-title":"Identification of a broad-spectrum arenavirus entry inhibitor","volume":"82","author":"Larson","year":"2008","journal-title":"J. Virol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"204ra131","DOI":"10.1126\/scitranslmed.3006827","article-title":"siRNA screen for genes that affect Junin virus entry uncovers voltage-gated calcium channels as a therapeutic target","volume":"5","author":"Lavanya","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"18734","DOI":"10.1074\/jbc.M802089200","article-title":"Unique small molecule entry inhibitors of hemorrhagic fever arenaviruses","volume":"283","author":"Lee","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"12701","DOI":"10.1073\/pnas.221447598","article-title":"The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1\/S1P","volume":"98","author":"Lenz","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e02429","DOI":"10.1128\/JVI.01118-21","article-title":"Screening of botanical drugs against Lassa virus entry","volume":"95","author":"Liu","year":"2021","journal-title":"J. Virol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3390\/v4010083","article-title":"The curious case of arenavirus entry, and its inhibition","volume":"4","author":"Nunberg","year":"2012","journal-title":"Viruses"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"V","DOI":"10.1007\/978-3-642-56029-3","article-title":"Arenaviruses. I. The epidemiology molecular and cell biology of arenaviruses. Introduction","volume":"262","author":"Oldstone","year":"2002","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.chom.2017.10.002","article-title":"NRP2 and CD63 are host factors for Lujo virus cell entry","volume":"22","author":"Raaben","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1056\/NEJMra022219","article-title":"Selective estrogen-receptor modulators\u2014mechanisms of action and application to clinical practice","volume":"348","author":"Riggs","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"19497","DOI":"10.1073\/pnas.1920551117","article-title":"CACNA1S haploinsufficiency confers resistance to New World arenavirus infection","volume":"117","author":"Sarute","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"6799","DOI":"10.1128\/JVI.00597-16","article-title":"Small-molecule fusion inhibitors bind the pH-sensing stable signal peptide-GP2 subunit Interface of the Lassa virus envelope glycoprotein","volume":"90","author":"Shankar","year":"2016","journal-title":"J. Virol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.apsb.2020.02.014","article-title":"Identification of the dietary supplement capsaicin as an inhibitor of Lassa virus entry","volume":"10","author":"Tang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1111\/boc.201200006","article-title":"Palmitoylation of virus proteins","volume":"104","author":"Veit","year":"2012","journal-title":"Biol. Cell."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.3390\/v4091802","article-title":"Animal models, prophylaxis, and therapeutics for arenavirus infections","volume":"4","author":"Vela","year":"2012","journal-title":"Viruses"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e00954","DOI":"10.1128\/JVI.00954-18","article-title":"Screening and identification of Lassa virus entry inhibitors from an FDA-approved drugs library","volume":"92","author":"Wang","year":"2018","journal-title":"J. Virol."},{"key":"ref31","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s12250-016-3815-4","article-title":"Structure-function relationship of the mammarenavirus envelope glycoprotein","volume":"31","author":"Wang","year":"2016","journal-title":"Virol. 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