RESUMO
Salicylanilides were found as selective inhibitors of interleukin-12p40 production in stimulated dendritic cells. The conversion of one of these bioactive salicylanilides into a comparably bioactive, chemically labeled derivative was achieved using a facile and systematic functional group derivatization strategy. This resulted in a tool reagent that was then employed in an affinity chromatography approach that resulted in the identification of the protein 14-3-3zeta as having selective affinity for the chromatography matrix that was derivatized with a salicylanilide that inhibited IL-12p40 production.
Assuntos
Proteínas 14-3-3/química , Marcadores de Afinidade/química , Subunidade p40 da Interleucina-12/antagonistas & inibidores , Salicilanilidas/química , Animais , Linhagem Celular , Cromatografia de Afinidade , Células Dendríticas , Subunidade p40 da Interleucina-12/biossíntese , Camundongos , RatosRESUMO
Interleukin (IL)-12p40, a subunit component of both IL-12 and IL-23, is being widely studied for its role in inflammatory disease. As part of an effort to profile cellular signaling pathways across different cell types, we report salicylanilide inhibitors of IL-12p40 production in stimulated dendritic cells. Based on a hypothesis that a desirable therapeutic profile is one that could block IL-12p40 but not IL-6 production, we engaged in directed analoging. This resulted in salicylanilides with similar IL-12p40 related potency but enhanced selectivity relative to IL-6 production.
