{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:57:03Z","timestamp":1787021823467,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009916","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Graduate School of Medical Sciences at the University of Groningen"},{"name":"Cock grant hadders stichting"},{"DOI":"10.13039\/501100005075","name":"university medical center groningen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005075","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005075","name":"university medical center groningen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005075","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Tomatidine, a natural steroidal alkaloid from unripe green tomatoes has been shown to exhibit many health benefits. We recently provided\n                    <jats:italic>in vitro<\/jats:italic>\n                    evidence that tomatidine reduces the infectivity of Dengue virus (DENV) and Chikungunya virus (CHIKV), two medically important arthropod-borne human infections for which no treatment options are available. We observed a potent antiviral effect with EC50 values of 0.82 \u03bcM for DENV-2 and 1.3 \u03bcM for CHIKV-LR. In this study, we investigated how tomatidine controls CHIKV infectivity. Using mass spectrometry, we identified that tomatidine induces the expression of p62, CD98, metallothionein and thioredoxin-related transmembrane protein 2 in Huh7 cells. The hits p62 and CD98 were validated, yet subsequent analysis revealed that they are not responsible for the observed antiviral effect. In parallel, we sought to identify at which step of the virus replication cycle tomatidine controls virus infectivity. A strong antiviral effect was seen when\n                    <jats:italic>in vitro<\/jats:italic>\n                    transcribed CHIKV RNA was transfected into Huh7 cells treated with tomatidine, thereby excluding a role for tomatidine during CHIKV cell entry. Subsequent determination of the number of intracellular viral RNA copies and viral protein expression levels during natural infection revealed that tomatidine reduces the RNA copy number and viral protein expression levels in infected cells. Once cells are infected, tomatidine is not able to interfere with active RNA replication yet it can reduce viral protein expression. Collectively, the results delineate that tomatidine controls viral protein expression to exert its antiviral activity. Lastly, sequential passaging of CHIKV in presence of tomatidine did not lead to viral resistance. Collectively, these results further emphasize the potential of tomatidine as an antiviral treatment towards CHIKV infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0009916","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T13:38:05Z","timestamp":1636637885000},"page":"e0009916","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-3580","authenticated-orcid":true,"given":"Berit","family":"Troost-Kind","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn J.","family":"van Hemert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"van de Pol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"van der Ende-Metselaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Merits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9644-288X","authenticated-orcid":true,"given":"Malte","family":"Borggrewe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7820-8624","authenticated-orcid":true,"given":"Izabela A.","family":"Rodenhuis-Zybert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-1448","authenticated-orcid":true,"given":"Jolanda M.","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"pntd.0009916.ref001","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3390\/v8060166","article-title":"Alphavirus Infection: Host Cell Shut-Off and Inhibition of Antiviral Responses","volume":"8","author":"JJ Fros","year":"2016","journal-title":"Viruses"},{"key":"pntd.0009916.ref002","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1172\/JCI84417","article-title":"Chikungunya virus: Epidemiology, replication, disease mechanisms, and prospective intervention strategies","volume":"127","author":"LA Silva","year":"2017","journal-title":"J Clin Invest"},{"key":"pntd.0009916.ref003","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.3389\/fmicb.2019.02881","article-title":"Recent Progress in Vaccine Development Against Chikungunya Virus","volume":"10","author":"S Gao","year":"2019","journal-title":"Front Microbiol"},{"key":"pntd.0009916.ref004","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3390\/v10050248","article-title":"Molecular and Clinical Characterization of Chikungunya Virus Infections in Southeast Mexico","volume":"10","author":"KA Gal\u00e1n-Huerta","year":"2018","journal-title":"Viruses"},{"key":"pntd.0009916.ref005","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nrmicro2368","article-title":"Biology and pathogenesis of chikungunya virus","volume":"8","author":"O Schwartz","year":"2010","journal-title":"Nat Rev Microbiol"},{"key":"pntd.0009916.ref006","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.antiviral.2015.06.017","article-title":"Towards antivirals against chikungunya virus","volume":"121","author":"R Abdelnabi","year":"2015","journal-title":"Antiviral Res"},{"key":"pntd.0009916.ref007","first-page":"235","volume-title":"Viruses","author":"BB Subudhi","year":"2018"},{"key":"pntd.0009916.ref008","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1371\/journal.pntd.0002471","article-title":"Identification of Novel Compounds Inhibiting Chikungunya Virus-Induced Cell Death by High Throughput Screening of a Kinase Inhibitor Library","volume":"7","author":"DJM Cruz","year":"2013","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0009916.ref009","doi-asserted-by":"crossref","first-page":"21899","DOI":"10.1074\/jbc.M802444200","article-title":"Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: Impairment of the maturation of the E2 surface glycoprotein","volume":"283","author":"S Ozden","year":"2008","journal-title":"J Biol Chem"},{"key":"pntd.0009916.ref010","first-page":"1849","article-title":"Ganetespib: Research and clinical development","volume":"8","author":"K Jhaveri","year":"2015","journal-title":"Onco Targets Ther"},{"key":"pntd.0009916.ref011","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/jmv.21663","article-title":"Parida M. 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