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The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the in vitro viral inhibitory activity of newly synthesized GPA derivatives against Zika virus (ZIKV), chikungunya virus (CHIKV), o\u2019nyong-nyong virus (ONNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Antiviral activity (EC50) and cytotoxicity (CC50) of the active compounds were determined using cell-based assays. The mechanism of action of the lead compound was investigated using binding and entry assays, cell-free virion pre-incubation, a virion destabilization assay, a liposome-based capsid protection assay, and molecular docking analysis. Results: Seven of the compounds were able to inhibit ZIKV and two compounds inhibited all four tested viruses. Among them, a teicoplanin pseudoaglycone derivative, compound 7, showed the strongest antiviral activity, inhibiting all four viruses at low micromolar concentrations. Mechanistic studies demonstrated that compound 7 acts during an early stage of ZIKV infection and inhibits low-pH-triggered virus\u2013liposome fusion. Molecular docking analysis suggested potential interactions between compound 7 and the viral envelope protein that could interfere with the conformational rearrangements required for membrane fusion. Conclusions: The present findings demonstrate that hydrophobic GPA derivatives, particularly compound 7, exhibit promising broad-spectrum antiviral activity in vitro. Whether similar mechanisms contribute to the antiviral activity against other viruses remains unknown. The studied GPA derivatives are promising candidates for further pre-clinical and clinical development as broad-spectrum antivirals.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070879","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:00:17Z","timestamp":1784548817000},"page":"879","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fusion Inhibition of Zika Virus Entry by a Teicoplanin Pseudoaglycone Derivative with Broad Antiviral Activity"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1176-5529","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Kopasz","sequence":"first","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"},{"name":"Faculty of Sciences, Institute of Biology, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 6, H-7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-7257","authenticated-orcid":false,"given":"Ilona","family":"Bereczki","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"},{"name":"Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Leiner","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"},{"name":"Faculty of Sciences, Institute of Biology, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 6, H-7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3887-5657","authenticated-orcid":false,"given":"Henrietta","family":"Papp","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1407-8960","authenticated-orcid":false,"given":"Eszter Bogl\u00e1rka","family":"L\u0151rincz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"},{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levente","family":"Sipos-Szab\u00f3","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Hungary"},{"name":"Medicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok krt. 2, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9429-4377","authenticated-orcid":false,"given":"Korn\u00e9lia","family":"Bod\u00f3","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nika","family":"Madai","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitta","family":"Zana","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9ka","family":"Erdei","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"Doctoral School of Chemistry, University of Debrecen, Egyetem t\u00e9r 1, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0442-1828","authenticated-orcid":false,"given":"Gyula","family":"Batta","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-4485","authenticated-orcid":false,"given":"Tam\u00e1s","family":"Kov\u00e1cs-\u00d6ller","sequence":"additional","affiliation":[{"name":"Faculty of Sciences, Institute of Biology, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 6, H-7624 Pecs, Hungary"},{"name":"J\u00e1nos Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-2669","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Varga","sequence":"additional","affiliation":[{"name":"Biological Nanochemistry Research Group, Institute of Materials and Environmental Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, H-1117 Budapest, Hungary"},{"name":"Department of Physical Chemistry and Materials Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3., H-1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4277-9481","authenticated-orcid":false,"given":"D\u00e1vid","family":"Bajusz","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok 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H-4032 Debrecen, Hungary"},{"name":"HUN-REN\u2013UD Molecular Recognition and Interaction Research Group, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anett","family":"Kuczmog","sequence":"additional","affiliation":[{"name":"National Laboratory of Virology, Szent\u00e1gothai Research Centre, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 20, 7624 Pecs, Hungary"},{"name":"Faculty of Sciences, Institute of Biology, University of P\u00e9cs, Ifj\u00fas\u00e1g \u00fatja 6, H-7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.meegid.2019.01.018","article-title":"ZIKA virus entry mechanisms in human cells","volume":"69","author":"Agrelli","year":"2019","journal-title":"Infect. 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