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Orientación selectiva del dominio AF9 YEATS por inhibidores de ciclopéptidos con conformación preorganizada
Yixiang Jiang1, Guochao Chen2,3, Xiao-Meng Li1
1Departments of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Journal of the American Chemical Society
|December 11, 2020
Resumen
Los investigadores desarrollaron un nuevo inhibidor de ciclopéptido, JYX-3, que se dirige selectivamente al dominio AF9 YEATS. Este avance ofrece una nueva vía prometedora para el desarrollo de fármacos contra enfermedades relacionadas con el dominio de YEATS como el cáncer.
Área de la Ciencia:
- La epigenética
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- Los dominios YEATS son lectores epigenéticos de la acetilación de la histona lisina (Kac) y la crotonilación (Kcr).
- Las interacciones YEATS-Kac/Kcr disfuncionales están implicadas en enfermedades humanas, incluido el cáncer.
- Los dominios de YEATS representan objetivos terapéuticos prometedores.
Objetivo del estudio:
- Desarrollar inhibidores selectivos para los dominios YEATS, diferenciando específicamente entre los dominios AF9 y ENL YEATS.
- Identificar nuevos sitios de unión para lograr la selectividad.
- Validar la eficacia de los inhibidores selectivos en contextos celulares.
Principales métodos:
- Identificación de un sitio alostérico proximal distinto de la bolsa de unión a la acilisina.
- Diseño y síntesis de ciclopéptidos preorganizados conformacionalmente.
- Ensayos bioquímicos para determinar la afinidad y la selectividad de la unión.
- Ensayos basados en células para evaluar el compromiso con el objetivo y los efectos funcionales.
Principales resultados:
- Se identificó un nuevo sitio proximal que diferencia a AF9 YEATS de ENL YEATS.
- La orientación combinada de la bolsa de acilisina y el sitio proximal produjo inhibidores selectivos de AF9 YEATS.
- El ciclopéptido JYX-3 demostró una afinidad de unión 38 veces mayor para AF9 YEATS que para ENL YEATS.
- JYX-3 involucró a AF9 en las células, interrumpió su reclutamiento de cromatina y suprimió la transcripción del gen objetivo.
Conclusiones:
- La inhibición selectiva de los dominios YEATS, en particular AF9, se puede lograr mediante la orientación tanto de la bolsa de acilisina como de un sitio alostérico adyacente.
- JYX-3 representa un inhibidor potente y selectivo de AF9 YEATS.
- Este estudio proporciona una base para el desarrollo de nuevas terapias para las patologías asociadas al dominio YEATS.
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