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Dirigirse a la conformación inactiva de la enzima: derivados del diquetoácido de arilo como una nueva clase de
Sijiu Liu1, Li-Fan Zeng, Li Wu
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
Journal of the American Chemical Society
|November 18, 2008
Resumen
Los investigadores identificaron los nuevos dicetoácidos de arilo como potentes inhibidores de la proteína tirosina fosfatasa 1B (PTP1B). Estos compuestos permeables a las células mejoran la señalización de la insulina, ofreciendo un nuevo potencial terapéutico para la diabetes y la obesidad.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Farmacología Farmacología.
- Biología Molecular Biología Molecular
Sus antecedentes:
- La proteína tirosina fosfatasa 1B (PTP1B) es un objetivo terapéutico clave para las enfermedades metabólicas y el cáncer.
- El desarrollo de inhibidores de PTP permeables a las células es un desafío debido a las limitaciones de los farmacóforos cargados actuales.
Objetivo del estudio:
- Identificar nuevos inhibidores de PTP1B con mejor permeabilidad celular y propiedades farmacológicas.
- Explorar los dicetoácidos de arilo y sus derivados diméricos como agentes potenciales de orientación de PTP1B.
Principales métodos:
- Identificación de los dicetoácidos de arilo como sustitutos de la fosfotirosina (pTyr).
- Síntesis y evaluación de dimeros de diquetoácido de arilo ligados a amida neutra.
- Estudios cinéticos para determinar los mecanismos de inhibición.
- Cristalografía de rayos X para dilucidar los modos de unión.
- Evaluación de la permeabilidad celular y la mejora de la señalización de la insulina en las células del hepatoma.
Principales resultados:
- Los dicetoácidos de arilo y sus derivados diméricos exhiben una potente actividad inhibidora de PTP1B.
- Estos compuestos actúan como inhibidores no competitivos de PTP1B.
- Las estructuras cristalinas revelan modos de unión distintos de los inhibidores en la conformación PTP1B inactiva.
- Los dicetoácidos diméricos de arilo son permeables a las células y mejoran la señalización de la insulina.
Conclusiones:
- Los dicetoácidos de arilo representan una nueva clase de inhibidores de PTP1B.
- Dirigirse a la conformación inactiva de PTP1B puede producir inhibidores con perfiles farmacológicos superiores.
- Estos hallazgos ofrecen una estrategia prometedora para el desarrollo de nuevas terapias para la diabetes y la obesidad.
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