N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin

Novel antiviral drugs are needed to prepare for infections from influenza A virus (IAV). Here, a series of N-[(thiophen-3-yl)methyl]benzamides, which target the hemagglutinin (HA)-mediated fusion process, is reported. The most active compound, VF-57a, displays a 50% effective concentration (EC50) of...

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Autores: Francesconi, Valeria, Rimaux, Silke, Valdivia, Aitor, Martín López, Juan, Escriche Molina, Celia, Mestdagh, Cato, Van Berwaer, Ria, Schurmans, Lieselotte, Verleye, Kaat, Noppen, Samuel, Lozano, Oscar, Stevaert, Annelies, Luque Garriga, F. Xavier, Niesens, Lieve, Vázquez Cruz, Santiago
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/227287
Acceso en línea:https://hdl.handle.net/2445/227287
Access Level:acceso abierto
Palabra clave:Inhibidors enzimàtics
Influenzavirus
Lligands
Enzyme inhibitors
Influenza viruses
Ligands
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spelling N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin Francesconi, ValeriaRimaux, SilkeValdivia, AitorMartín López, JuanEscriche Molina, CeliaMestdagh, CatoVan Berwaer, RiaSchurmans, LieselotteVerleye, KaatNoppen, SamuelLozano, OscarStevaert, AnneliesLuque Garriga, F. XavierNiesens, LieveVázquez Cruz, SantiagoInhibidors enzimàticsInfluenzavirusLligandsEnzyme inhibitorsInfluenza virusesLigandsNovel antiviral drugs are needed to prepare for infections from influenza A virus (IAV). Here, a series of N-[(thiophen-3-yl)methyl]benzamides, which target the hemagglutinin (HA)-mediated fusion process, is reported. The most active compound, VF-57a, displays a 50% effective concentration (EC50) of∼0.8 <em>μ</em>M and an antiviral selectivity index >130 in Madin−Darby canine kidney (MDCK) cells infected with A/H1N1 virus. VF-57a proved to be a strong inhibitor of A/H1N1 and A/H5N1 pseudovirus entry (EC50 values of 0.3 and 0.8 <em>μ</em>M, respectively). Cell−cell fusion assays in HA-expressing cells, surface plasmon resonance-based assessment of HA protein refolding, and resistance studies suggested that VF-57a prevents the conformational change of HA at acidic pH. Molecular modeling highlighted the role of the dimethylthiophene moiety and the amide-based tether in anchoring to the binding cavity of HA. Our findings support the further development of this class of IAV fusion inhibitors against A/H1N1 and A/H5N1 viruses.American Chemical Society2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/227287Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1021/acs.jmedchem.5c01357Journal of Medicinal Chemistry, 2025, vol. 68, p. 18491-18518https://doi.org/10.1021/acs.jmedchem.5c01357cc-by (c) Valeria Francesconi, et al., 2025https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2272872026-05-27T06:46:51Z
dc.title.none.fl_str_mv N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
title N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
spellingShingle N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
Francesconi, Valeria
Inhibidors enzimàtics
Influenzavirus
Lligands
Enzyme inhibitors
Influenza viruses
Ligands
title_short N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
title_full N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
title_fullStr N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
title_full_unstemmed N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
title_sort N‑[(Thiophen-3-yl)methyl]benzamides as fusion inhibitors of influenza virus targeting H1 and H5 hemagglutinin
dc.creator.none.fl_str_mv Francesconi, Valeria
Rimaux, Silke
Valdivia, Aitor
Martín López, Juan
Escriche Molina, Celia
Mestdagh, Cato
Van Berwaer, Ria
Schurmans, Lieselotte
Verleye, Kaat
Noppen, Samuel
Lozano, Oscar
Stevaert, Annelies
Luque Garriga, F. Xavier
Niesens, Lieve
Vázquez Cruz, Santiago
author Francesconi, Valeria
author_facet Francesconi, Valeria
Rimaux, Silke
Valdivia, Aitor
Martín López, Juan
Escriche Molina, Celia
Mestdagh, Cato
Van Berwaer, Ria
Schurmans, Lieselotte
Verleye, Kaat
Noppen, Samuel
Lozano, Oscar
Stevaert, Annelies
Luque Garriga, F. Xavier
Niesens, Lieve
Vázquez Cruz, Santiago
author_role author
author2 Rimaux, Silke
Valdivia, Aitor
Martín López, Juan
Escriche Molina, Celia
Mestdagh, Cato
Van Berwaer, Ria
Schurmans, Lieselotte
Verleye, Kaat
Noppen, Samuel
Lozano, Oscar
Stevaert, Annelies
Luque Garriga, F. Xavier
Niesens, Lieve
Vázquez Cruz, Santiago
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Inhibidors enzimàtics
Influenzavirus
Lligands
Enzyme inhibitors
Influenza viruses
Ligands
topic Inhibidors enzimàtics
Influenzavirus
Lligands
Enzyme inhibitors
Influenza viruses
Ligands
description Novel antiviral drugs are needed to prepare for infections from influenza A virus (IAV). Here, a series of N-[(thiophen-3-yl)methyl]benzamides, which target the hemagglutinin (HA)-mediated fusion process, is reported. The most active compound, VF-57a, displays a 50% effective concentration (EC50) of∼0.8 <em>μ</em>M and an antiviral selectivity index >130 in Madin−Darby canine kidney (MDCK) cells infected with A/H1N1 virus. VF-57a proved to be a strong inhibitor of A/H1N1 and A/H5N1 pseudovirus entry (EC50 values of 0.3 and 0.8 <em>μ</em>M, respectively). Cell−cell fusion assays in HA-expressing cells, surface plasmon resonance-based assessment of HA protein refolding, and resistance studies suggested that VF-57a prevents the conformational change of HA at acidic pH. Molecular modeling highlighted the role of the dimethylthiophene moiety and the amide-based tether in anchoring to the binding cavity of HA. Our findings support the further development of this class of IAV fusion inhibitors against A/H1N1 and A/H5N1 viruses.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/227287
url https://hdl.handle.net/2445/227287
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1021/acs.jmedchem.5c01357
Journal of Medicinal Chemistry, 2025, vol. 68, p. 18491-18518
https://doi.org/10.1021/acs.jmedchem.5c01357
dc.rights.none.fl_str_mv cc-by (c) Valeria Francesconi, et al., 2025
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Valeria Francesconi, et al., 2025
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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