<i>N</i>-[(Thiophen-3-yl)methyl]benzamides as Fusion Inhibitors of Influenza Virus Targeting H1 and H5 Hemagglutinins
Novel antiviral drugs are needed to prepare for infections from influenza A virus (IAV). Here, a series of <i>N</i>-[(thiophen-3-yl)methyl]benzamides, which target the hemagglutinin (HA)-mediated fusion process, is reported. The most active compound, <b>VF-57a</b>, displays a 50% effective concentration (EC<sub>50</sub>) of ∼0.8 μM and an antiviral selectivity index >130 in Madin-Darby canine kidney (MDCK) cells infected with A/H1N1 virus. <b>VF-57a</b> proved to be a strong inhibitor of A/H1N1 and A/H5N1 pseudovirus entry (EC<sub>50</sub> values of 0.3 and 0.8 μM, respectively). Cell-cell fusion assays in HA-expressing cells, surface plasmon resonance-based assessment of HA protein refolding, and resistance studies suggested that <b>VF-57a</b> 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.
Authors
- Santiago Vázquez (ORCID: https://orcid.org/0000-0002-9296-6026)
- Ria Van Berwaer
- Valeria Francesconi (ORCID: https://orcid.org/0000-0002-1414-9266)
- Cato Mestdagh (ORCID: https://orcid.org/0000-0002-4068-4975)
- Óscar Lozano
- Annelies Stevaert (ORCID: https://orcid.org/0000-0003-3316-2826)
- F. Javier Luque (ORCID: https://orcid.org/0000-0002-8049-3567)
- Sam Noppen (ORCID: https://orcid.org/0000-0002-2831-5042)
- Juan San Martín (ORCID: https://orcid.org/0000-0003-4457-5124)
- Lieve M. J. Naesens (ORCID: https://orcid.org/0000-0001-9742-9302)
- Aitor Valdivia (ORCID: https://orcid.org/0000-0003-4862-0850)
- Celia Escriche (ORCID: https://orcid.org/0009-0004-2968-7341)
- Silke Rimaux (ORCID: https://orcid.org/0000-0002-1802-2246)
- Lieselotte Schurmans
- Kaat Verleye (ORCID: https://orcid.org/0009-0002-7670-9158)
Institutions
- Rega Institute for Medical Research (BE)
- Computational Physics (United States) (US)
- Institut de Biomedicina de la Universitat de Barcelona
- Universitat de Barcelona (ES)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01357
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundació la Marató de TV3
- Ministerio de Ciencia, Innovación y Universidades
- Fonds Wetenschappelijk Onderzoek
- Agència de Gestió d'Ajuts Universitaris i de Recerca