Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Sci Rep ; 7(1): 1763, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28496125

RESUMEN

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies underscore that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides.


Asunto(s)
Sistemas de Liberación de Medicamentos , Hidrocarburos/química , Espacio Intracelular/metabolismo , Lípidos/química , Complejos Multiproteicos/metabolismo , Péptidos/química , Cationes , Supervivencia Celular , Endosomas/metabolismo , Genes Reporteros , Células HEK293 , Humanos , Concentración 50 Inhibidora , Biblioteca de Péptidos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Piridinas/química , Activación Transcripcional/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA