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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Detalhes bibliográficos
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 documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/227287
Acesso em linha:https://hdl.handle.net/2445/227287
Access Level:Acceso aberto
Palavra-chave:Inhibidors enzimàtics
Influenzavirus
Lligands
Enzyme inhibitors
Influenza viruses
Ligands
Descrição
Resumo: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.

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