N-benzamides as Influenza Virus Fusion Inhibitors Acting on H1 and H5 Hemagglutinins

Rimaux, S.; Valdivia, A.; Martin-Lopez, J.; Francesconi, V.; Escriche, C.; Mestdagh, C.; Van Berwaer, R.; Schurmans, L.; Verleye, K.; Noppen, S.; Lozano, O.; Stevaert, A.; Luque, F. J.; Naesens, L.; Vazquez, S.

doi:10.1101/2025.07.28.667118

bioRxiv · 10.1101/2025.07.28.667118

N-benzamides as Influenza Virus Fusion Inhibitors Acting on H1 and H5 Hemagglutinins

Rimaux, S.·Valdivia, A.·Martin-Lopez, J.·Francesconi, V.·Escriche, C.·Mestdagh, C.·Van Berwaer, R.·Schurmans, L.·Verleye, K.·Noppen, S.·Lozano, O.·Stevaert, A.·Luque, F. J.·Naesens, L.·Vazquez, S.

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Abstract

Novel antiviral drugs are needed to prepare against infections from influenza A virus (IAV). Here a series of N-[(thiophen-3-yl)methylbenzamides 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 M and 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 {micro}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 modelling highlighted the role of the dimethylthiophene moiety and the amide-based tether in the anchoring to the binding cavity of HA. Our findings support further development of this class of IAV fusion inhibitors against A/H1N1 and A/H5N1 viruses.

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Rimaux, S., Valdivia, A., Martin-Lopez, J., Francesconi, V., Escriche, C., Mestdagh, C., Van Berwaer, R., Schurmans, L., Verleye, K., Noppen, S., Lozano, O., Stevaert, A., Luque, F. J., Naesens, L., Vazquez, S.. 2025-07-28. N-benzamides as Influenza Virus Fusion Inhibitors Acting on H1 and H5 Hemagglutinins. https://doi.org/10.1101/2025.07.28.667118

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