RESUMEN
New structural classes of K(V)1.3 and IK-1 ion channel blockers have been identified based on a virtual high throughput screening approach using a homology model of KcsA. These compounds display inhibitory effects on T-cell and/or keratinocyte proliferation and immunosuppressant activity within a DTH animal model.
Asunto(s)
Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Canal de Potasio Kv1.3/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/metabolismo , Inmunosupresores/clasificación , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/química , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/fisiología , Queratinocitos/efectos de los fármacos , Queratinocitos/fisiología , Canal de Potasio Kv1.3/química , Canal de Potasio Kv1.3/fisiología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/clasificaciónRESUMEN
Human Vgamma9delta2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens. In contrast to alphabeta T cells, gammadelta T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner. Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria. However, natural occurring gammadelta T cell ligands from other bacterial species were not characterized so far. Here, we describe the structural identification of the two compounds responsible for the gammadelta T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M(r) 275 homologue TUBag2. In addition, E. coli phosphoantigens exert bioactivities on gammadelta T cells with similar potencies to the mycobacterial phosphoantigens at 5-15 nm concentration. Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E. coli. Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human gammadelta T lymphocytes.
