RESUMEN
A chemical-genetic method for the generation of target-specific protein kinase inhibitors has been developed recently. This strategy utilizes a functionally silent active-site mutation to sensitize a target kinase to inhibition by a small molecule that does not inhibit wild-type kinases. Tyrosine and serine/threonine kinases are equally amenable to the drug-sensitization approach, which has been used to generate selective inhibitors of mutant Src-family kinases, Abl-family kinases, cyclin-dependent kinases, mitogen-activated kinases, p21-activated kinases and Ca(2+)/calmodulin-dependent kinases. The designed inhibitors are specific for the sensitized kinase in a cellular background where the wild-type kinase has been inactivated. By these means, kinase-sensitization has been used systematically to generate and analyze conditional alleles of several yeast protein kinases in vivo.
Asunto(s)
Proteínas Portadoras/síntesis química , Péptidos y Proteínas de Señalización Intracelular , Proteínas Quinasas/genética , Proteínas Quinasas/uso terapéutico , Animales , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/tendencias , Diseño de Fármacos , Terapia Genética/métodos , Terapia Genética/tendencias , Humanos , Mutagénesis , Proteínas Quinasas/efectos de los fármacosRESUMEN
Small molecules that modulate the activity of biological signaling molecules can be powerful probes of signal transduction pathways. Highly specific molecules with high affinity are difficult to identify because of the conserved nature of many protein active sites. A newly developed approach to discovery of such small molecules that relies on protein engineering and chemical synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-transmembrane receptors, nuclear hormone receptors, and others). Such chemical genetic tools combine the advantages of traditional genetics and the unparalleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.
Asunto(s)
Técnicas Genéticas , Ligandos , Ingeniería de Proteínas , Alelos , Secuencia de Aminoácidos , Animales , Sitios de Unión , GTP Fosfohidrolasas/química , Humanos , Cinesinas/química , Cinesinas/genética , Modelos Biológicos , Modelos Moleculares , Datos de Secuencia Molecular , Miosinas/química , Miosinas/genética , Proteínas Quinasas/química , Proteínas/síntesis química , Transducción de SeñalRESUMEN
Targeting the fusogenic machinery of HIV with unnatural ligand libraries.
