Salicylamides as RNA-Dependent RNA Polymerase Inhibitors with Antiviral Activity against West Nile and Zika Viruses
Abstract Mosquito-transmitted orthoflaviviruses constitute an escalating global threat to public health, for which no approved antiviral therapies exist. Here, we identify the salicylanilide derivative S1 as a West Nile virus (WNV) RNA-dependent RNA-polymerase (RdRp) inhibitor. Chemical optimization of S1 yielded compound S7, which inhibited WNV RdRp activity and displayed antiviral efficacy in Vero cells (EC50 of 3.0 μM; CC50 > 100 μM). S7 and related analogues inhibited Zika virus (ZIKV) RdRp, and this enzymatic inhibition translated into antiviral activity in cell-based assays. Compared with niclosamide, as reference salicylanilide, compound S7 exerted lower impact on mitochondria, reduced cytotoxicity and no induction of apoptosis. Molecular modelling support binding within the polymerase N-pocket, with key contributing residues being highly conserved in both WNV and ZIKV polymerases. Site-directed mutagenesis further supported the importance of N-pocket residues for S7 binding. Therefore, the S7-scaffold constitutes a promising antiviral chemotype against orthoflaviviruses.
Authors
- Teresa Poderoso (ORCID: https://orcid.org/0000-0002-1406-000X)
- María‐Jesús Pérez‐Pérez (ORCID: https://orcid.org/0000-0003-1336-7760)
- Tereza Kauerová (ORCID: https://orcid.org/0000-0003-2854-511X)
- Eva‐María Priego (ORCID: https://orcid.org/0000-0001-9470-4508)
- Flavia Caridi (ORCID: https://orcid.org/0000-0001-6378-9983)
- Marta Gargantilla (ORCID: https://orcid.org/0000-0002-2901-7039)
- Ernesto Quesada (ORCID: https://orcid.org/0000-0001-6886-0523)
- Miguel A. Martín-Acebes (ORCID: https://orcid.org/0000-0001-6015-3613)
- Péter Kollár (ORCID: https://orcid.org/0000-0003-2265-1528)
- Rubén Agudo (ORCID: https://orcid.org/0000-0002-4784-3318)
- Natalia del Río (ORCID: https://orcid.org/0000-0002-6722-248X)
- Estela Escribano-Romero (ORCID: https://orcid.org/0000-0002-5036-7607)
- Alejandra Álvarez-Mínguez
- Álvaro Rodríguez-Tacón
Institutions
- Universidad San Pablo CEU (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Masaryk University (CZ)
- Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (ES)
- Instituto de Química Médica (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01236
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Comunidad de Madrid
- Ministerio de Ciencia, Innovación y Universidades
- European Regional Development Fund
- NextGenerationEU