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Las sustancias químicas neuroprotectoras P7C3 funcionan activando la enzima que limita la velocidad en el rescate de
Gelin Wang1, Ting Han1, Deepak Nijhawan2
1Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
Cell
|September 13, 2014
Resumen
Las sustancias químicas neuroprotectoras P7C3 mejoran la supervivencia neuronal al aumentar los niveles de nicotinamida adenina dinucleótido (NAD). Lo logran mediante la activación de la enzima NAMPT, ofreciendo una nueva estrategia terapéutica para las enfermedades neurodegenerativas.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- La bioquímica es la bioquímica.
- Farmacología Farmacología.
Sus antecedentes:
- La clase de sustancias químicas P7C3 promueve la supervivencia neuronal en modelos de neurodegeneración.
- El mecanismo preciso de la neuroprotección P7C3 aún no se ha aclarado.
Objetivo del estudio:
- Determinar el mecanismo molecular por el cual los compuestos P7C3 ejercen sus efectos neuroprotectores.
- Para identificar el objetivo celular específico de los derivados activos del P7C3.
Principales métodos:
- Modificación química de un derivado activo de P7C3 con las funcionalidades de fotocrosslinking (benzofenona) y química de clic (alquina).
- Identificación de proteínas basada en afinidad para identificar a los socios de unión.
- Los ensayos de actividad enzimática utilizan la nicotinamida fosforibosiltransferasa purificada (NAMPT).
- Pruebas basadas en células para evaluar los niveles de NAD y la protección contra la toxicidad inducida por la doxorubicina.
Principales resultados:
- Se sintetizó un derivado modificado de P7C3 y se utilizó para identificar su objetivo de unión.
- Se encontró que el derivado P7C3 se une a la nicotinamida fosforibosiltransferasa (NAMPT), la enzima clave en el salvamento de NAD.
- La administración de P7C3 restauró los niveles de NAD agotados por la doxorubicina y protegió a las células de la toxicidad.
- Las variantes activas de P7C3 aumentaron la actividad de la enzima NAMPT purificada.
Conclusiones:
- La neuroprotección P7C3 está mediada por la activación de NAMPT, lo que lleva a un aumento de los niveles intracelulares de NAD.
- Este mecanismo ofrece un nuevo enfoque terapéutico para las afecciones neurodegenerativas caracterizadas por el agotamiento de NAD.
- Dirigirse a la vía de salvamento del NAMPT representa una estrategia prometedora para mejorar la resiliencia neuronal.
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