{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:47:01Z","timestamp":1760060821505,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Respiratory syncytial virus (RSV) infections have a significant impact on global health. Despite of recent advancements, the current treatment options for managing severe RSV infections remain primarily limited to supportive care, emphasizing the high priority for the development of effective antiviral therapies. Antiviral activity of 3,3\u2032,4,4\u2032,5,5\u2032-hexahydroxy-trans-stilbene (HHS), a synthetic polyhydroxyphenol, has previously been demonstrated against SARS-CoV-2. In this study, we provide evidence for a direct virucidal effect of HHS against RSV infection in permissive HEp-2 cells in vitro. HHS, with an IC50 of 3.44 \u03bcM, efficiently inhibited HEp-2 cell infection with no sign of toxicity at least up to 25 \u03bcM. Interestingly, resveratrol, a polyhydroxyphenol analogue, was less efficient. Mode of action experiments revealed that HHS directly interacts with RSV particles, indicating that its virucidal activity is based on this interaction rather than affecting HEp-2 cells or post-infection processes. Together with previous data, our results suggest a broad antiviral activity of HHS against different respiratory viruses. Further studies are necessary to unveil the exact mechanism and evaluate the potential of HHS in the treatment of severe respiratory virus infections.<\/jats:p>","DOI":"10.3390\/v17101287","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T10:27:53Z","timestamp":1758623273000},"page":"1287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virucidal Potential of 3,3\u2032,4,4\u2032,5,5\u2032-Hexahydroxy-trans-Stilbene Against Respiratory Syncytial Virus"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3826-5800","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"B\u00e1nki","sequence":"first","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1497-5170","authenticated-orcid":false,"given":"Leonie","family":"Wolf","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"M\u00fcllauer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Geisler-Moroder","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8011-5825","authenticated-orcid":false,"given":"Wegene","family":"Borena","sequence":"additional","affiliation":[{"name":"Institute of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4874-970X","authenticated-orcid":false,"given":"Thomas","family":"Szekeres","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1016\/S0140-6736(22)00478-0","article-title":"Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: A systematic analysis","volume":"399","author":"Li","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Venkatesan, P. (2023). First RSV vaccine approvals. Lancet Microbe, 4.","DOI":"10.1016\/S2666-5247(23)00195-7"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1056\/NEJMoa1211917","article-title":"Respiratory syncytial virus and recurrent wheeze in healthy preterm infants","volume":"368","author":"Blanken","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1056\/NEJMoa2309189","article-title":"Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants","volume":"389","author":"Drysdale","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gatt, D., Martin, I., AlFouzan, R., and Moraes, T.J. (2023). Prevention and Treatment Strategies for Respiratory Syncytial Virus (RSV). Pathogens, 12.","DOI":"10.3390\/pathogens12020154"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.phymed.2008.06.008","article-title":"Synergism between natural products and antibiotics against infectious diseases","volume":"15","author":"Hemaiswarya","year":"2008","journal-title":"Phytomedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/j.biopha.2017.09.084","article-title":"Comprehensive review on the antimicrobial potency of the plant polyphenol Resveratrol","volume":"95","author":"Bostanghadiri","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.ijantimicag.2019.02.015","article-title":"Antibacterial and antifungal properties of resveratrol","volume":"53","author":"Vestergaard","year":"2019","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0166-3542(99)00042-X","article-title":"Resveratrol inhibition of herpes simplex virus replication","volume":"43","author":"Docherty","year":"1999","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.antiviral.2006.07.004","article-title":"Resveratrol inhibition of varicella-zoster virus replication in vitro","volume":"72","author":"Docherty","year":"2006","journal-title":"Antivir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.antiviral.2004.03.002","article-title":"3,4\u2032,5-Trihydroxy-trans-stilbene (resveratrol) inhibits human cytomegalovirus replication and virus-induced cellular signaling","volume":"63","author":"Evers","year":"2004","journal-title":"Antivir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7115","DOI":"10.3390\/molecules15107115","article-title":"Inhibitory effects of resveratrol on the Epstein-Barr virus lytic cycle","volume":"15","author":"Yiu","year":"2010","journal-title":"Molecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1515\/nipt-2023-0012","article-title":"Resveratrol and its analogs suppress HIV replication, oxidative stress, and inflammation in macrophages","volume":"2","author":"Kumar","year":"2023","journal-title":"NeuroImmune Pharm. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1086\/429694","article-title":"Inhibition of influenza A virus replication by resveratrol","volume":"191","author":"Palamara","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ter Ellen, B.M., Dinesh Kumar, N., Bouma, E.M., Troost, B., van de Pol, D.P.I., van der Ende-Metselaar, H.H., Apperloo, L., van Gosliga, D., van den Berge, M., and Nawijn, M.C. (2021). Resveratrol and Pterostilbene Inhibit SARS-CoV-2 Replication in Air-Liquid Interface Cultured Human Primary Bronchial Epithelial Cells. Viruses, 13.","DOI":"10.3390\/v13071335"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5571","DOI":"10.1016\/j.bmc.2004.08.008","article-title":"Resveratrol analogues as selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationship","volume":"12","author":"Murias","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_17","first-page":"1621","article-title":"Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: Inhibition of ribonucleotide reductase activity","volume":"19","author":"Saiko","year":"2008","journal-title":"Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1038\/jid.2009.376","article-title":"3,3\u2032,4,4\u2032,5,5\u2032-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model","volume":"130","author":"Paulitschke","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Fischhuber, K., Banki, Z., Kimpel, J., Kragl, N., Rossler, A., Bolze, A., Muellauer, B., Angerer, J., Nagy, G., and Nagy, E. (2023). Antiviral Potential of Azelastine against Major Respiratory Viruses. Viruses, 15.","DOI":"10.3390\/v15122300"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Srinivasan, V., Brognaro, H., Prabhu, P.R., de Souza, E.E., Gunther, S., Reinke, P.Y.A., Lane, T.J., Ginn, H., Han, H., and Ewert, W. (2022). Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03737-7"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Reshamwala, D., Shroff, S., Sheik Amamuddy, O., Laquintana, V., Denora, N., Zacheo, A., Lampinen, V., Hytonen, V.P., Tastan Bishop, O., and Krol, S. (2021). Polyphenols Epigallocatechin Gallate and Resveratrol, and Polyphenol-Functionalized Nanoparticles Prevent Enterovirus Infection through Clustering and Stabilization of the Viruses. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081182"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lin, C.J., Lin, H.J., Chen, T.H., Hsu, Y.A., Liu, C.S., Hwang, G.Y., and Wan, L. (2015). Polygonum cuspidatum and its active components inhibit replication of the influenza virus through toll-like receptor 9-induced interferon beta expression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125288"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1039\/D3FO05131E","article-title":"Resveratrol inhibits respiratory syncytial virus replication by targeting heparan sulfate proteoglycans","volume":"15","author":"Xiong","year":"2024","journal-title":"Food Funct."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zlodeeva, P.D., Shekunov, E.V., Ostroumova, O.S., and Efimova, S.S. (2023). The Degree of Hydroxylation of Phenolic Rings Determines the Ability of Flavonoids and Stilbenes to Inhibit Calcium-Mediated Membrane Fusion. Nutrients, 15.","DOI":"10.3390\/nu15051121"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jager, W., Kicker, E., Hardt, M., Gawish, R., Gattinger, P., Bohmdorfer, M., Knapp, S., Valenta, R., Zatloukal, K., and Szekeres, T. (2023). Identification of a Synthetic Polyhydroxyphenolic Resveratrol Analogue, 3,3\u2032,4,4\u2032,5,5\u2032-Hexahydroxy-trans-Stilbene with Anti-SARS-CoV-2 Activity. Molecules, 28.","DOI":"10.3390\/molecules28062612"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1002\/jmv.24271","article-title":"A resveratrol analog termed 3,3\u2032,4,4\u2032,5,5\u2032-hexahydroxy-trans-stilbene is a potent HIV-1 inhibitor","volume":"87","author":"Han","year":"2015","journal-title":"J. Med. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1007\/s00705-011-0989-9","article-title":"Antiviral activity and possible mechanisms of action of pentagalloylglucose (PGG) against influenza A virus","volume":"156","author":"Liu","year":"2011","journal-title":"Arch. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.2174\/092986709788682065","article-title":"Antiviral and virucidal activities of natural products","volume":"16","author":"Arakawa","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.antiviral.2010.06.005","article-title":"Inhibition of arenavirus infection by thiuram and aromatic disulfides","volume":"87","author":"Sepulveda","year":"2010","journal-title":"Antivir. Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:47:40Z","timestamp":1760035660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/10\/1287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["v17101287"],"URL":"https:\/\/doi.org\/10.3390\/v17101287","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,9,23]]}}}