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Síntesis Química Total y Plegado de las Variantes All-l y All-d del KRas Oncogénico ((G12V)
Adam M Levinson1, John H McGee2, Andrew G Roberts
1Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medical College , New York, New York 10065, United States.
Journal of the American Chemical Society
|April 28, 2017
Resumen
Los investigadores sintetizaron formas de imagen especular de las proteínas Ras (KRas) que impulsan el cáncer. Estas proteínas enantioméricas pueden plegarse y unirse a moléculas, lo que permite nuevas estrategias terapéuticas contra objetivos de cáncer difíciles.
Área de la Ciencia:
- La bioquímica
- Biología Química
- En el campo de la oncología
Sus antecedentes:
- Las proteínas Ras son GTPasas cruciales que regulan el crecimiento y la supervivencia celular.
- Las proteínas Ras mutadas están implicadas en ~ 30% de los cánceres humanos, impulsando la proliferación incontrolada.
- Ras ha sido históricamente desafiante para apuntar terapéuticamente debido a sus propiedades bioquímicas.
Objetivo del estudio:
- Para lograr la síntesis química total de las variantes de todos los aminoácidos l y d del KRas oncogénico ((G12V).
- Investigar las propiedades bioquímicas y la competencia funcional de estas proteínas Ras enantioméricas.
- Establecer una base para el desarrollo de nuevas estrategias terapéuticas contra el Ras oncogénico.
Principales métodos:
- Se empleó la síntesis de péptidos en fase sólida basada en Fmoc para la construcción de proteínas.
- Para el ensamblaje se utilizó la ligadura química nativa y la activación mediada por isonitril.
- Las variantes enantioméricas KRas ((G12V) fueron sintetizadas y caracterizadas bioquímicamente.
Principales resultados:
- Se han sintetizado con éxito variantes de todos los aminoácidos I y D biotinilados KRas (G12V).
- Se demostró que ambos enantiómeros de KRas ((G12V) pueden plegarse y unirse a sustratos de nucleótidos.
- Se ha observado enantiodiscriminación en las interacciones entre el sustrato nucleótido y el socio de unión.
Conclusiones:
- La síntesis y la validación funcional de las KRas enantioméricas proporcionan una nueva herramienta bioquímica.
- Este trabajo permite la visualización de la superficie de la levadura en imagen especular para identificar los ligandos de péptidos all-d.
- Estos hallazgos ofrecen una nueva vía prometedora para el desarrollo de terapias contra los KR oncogénicos.
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