Salicylamides as RNA-Dependent RNA Polymerase Inhibitors with Antiviral Activity against West Nile and Zika Viruses
Natalia del Río, Álvaro Rodríguez-Tacón, Estela Escribano-Romero, Alejandra Álvarez-Mínguez, Marta Gargantilla, Flavia Caridi, Teresa Poderoso, Ernesto Quesada, Tereza Kauerová, Peter Kollár, Miguel A. Martín-Acebes, Eva-María Priego, Rubén Agudo, María-Jesús Pérez-PérezAbstract
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.