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Eur J Med Chem ; 157: 1202-1213, 2018 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-30193218

RESUMEN

The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in host cells and is a promising drug target. Through an enzymatic screen of the National Institute of Health clinical compound library, we report the discovery of zafirlukast, an FDA approved treatment for asthma, as an inhibitor for the WNV NS2B-NS3 protease. Zafirlukast was determined to inhibit the protease through a mixed mode mechanism with an IC50 value of 32 µM. A structure activity relationship study of zafirlukast revealed the cyclopentyl carbamate and N-aryl sulfonamide as structural elements crucial for NS2B-NS3 protease inhibition. Replacing the cyclopentyl with a phenyl improved inhibition, resulting in an IC50 of 22 µM. Experimental and computational docking analysis support the inhibition model of zafirlukast and analogs binding at an allosteric site on the NS3 protein, thereby disrupting the NS2B cofactor from binding, resulting in protease inhibition.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Inhibidores de Proteasas/farmacología , Compuestos de Tosilo/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Virus del Nilo Occidental/efectos de los fármacos , Virus del Nilo Occidental/enzimología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Indoles , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Fenilcarbamatos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/metabolismo , Serina Endopeptidasas/metabolismo , Relación Estructura-Actividad , Sulfonamidas , Compuestos de Tosilo/síntesis química , Compuestos de Tosilo/química , Proteínas no Estructurales Virales/metabolismo
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