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dc.contributor.authorBlockus, Sebastian
dc.contributor.authorSake, Svenja M
dc.contributor.authorWetzke, Martin
dc.contributor.authorGrethe, Christina
dc.contributor.authorGraalmann, Theresa
dc.contributor.authorPils, Marina
dc.contributor.authorLe Goffic, Ronan
dc.contributor.authorGalloux, Marie
dc.contributor.authorProchnow, Hans
dc.contributor.authorRox, Katharina
dc.contributor.authorHüttel, Stephan
dc.contributor.authorRupcic, Zeljka
dc.contributor.authorWiegmann, Bettina
dc.contributor.authorDijkman, Ronald
dc.contributor.authorRameix-Welti, Marie-Anne
dc.contributor.authorEléouët, Jean-François
dc.contributor.authorDuprex, W Paul
dc.contributor.authorThiel, Volker
dc.contributor.authorHansen, Gesine
dc.contributor.authorBrönstrup, Mark
dc.contributor.authorHaid, Sibylle
dc.contributor.authorPietschmann, Thomas
dc.date.accessioned2020-05-25T14:26:43Z
dc.date.available2020-05-25T14:26:43Z
dc.date.issued2020-03-18
dc.identifier.citationAntiviral Res. 2020;177:104774. doi:10.1016/j.antiviral.2020.104774.en_US
dc.identifier.pmid32197980
dc.identifier.doi10.1016/j.antiviral.2020.104774
dc.identifier.urihttp://hdl.handle.net/10033/622273
dc.description.abstractAcute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC50s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAntiviral activityen_US
dc.subjectHuman respiratory syncytial virus (hRSV)en_US
dc.subjectLabyrinthopeptinen_US
dc.subjectLanthipeptideen_US
dc.subjectVirolyticen_US
dc.subjectVirus entryen_US
dc.titleLabyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry.en_US
dc.typeArticleen_US
dc.identifier.eissn1872-9096
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
dc.identifier.journalAntiviral researchen_US
dc.source.volume177
dc.source.beginpage104774
dc.source.endpage
dc.source.journaltitleAntiviral research
dc.source.countryNetherlands


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Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International