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Cribado basado en fragmentos dirigido al sitio para el descubrimiento de estabilizadores de interacción

Eline Sijbesma¹, Kenneth K Hallenbeck², Seppe Leysen¹

¹Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) , Eindhoven University of Technology , 5600 MB Eindhoven , The Netherlands.

Journal of the American Chemical Society

|February 2, 2019

Resumen

Los investigadores desarrollaron un nuevo método de enlace para descubrir pequeñas moléculas que estabilizan las interacciones proteína-proteína (IPP). Esta técnica identificó con éxito estabilizadores para la interacción de 14-3-3σ y el receptor de estrógeno α, crucial en el cáncer de mama.

Área de la Ciencia:

Descubrimiento y desarrollo de fármacos
Biología molecular
Biología estructural

Sus antecedentes:

La modulación de las interacciones proteína-proteína (IPP) con moléculas pequeñas es una estrategia clave en el descubrimiento de fármacos.
La estabilización de PPI ofrece ventajas sobre la inhibición, incluida una mayor selectividad al dirigirse a interfaces proteicas específicas.

Objetivo del estudio:

Aplicar una técnica de cribado de captura de disulfuro (tethering) para identificar los fragmentos que estabilizan la interacción entre el 14-3-3σ y el receptor de estrógeno α (ERα).
Explorar la estabilización de PPI como estrategia terapéutica para el cáncer de mama, dirigida a la regulación 14-3-3σ de ERα.

Principales métodos:

Se utilizó un ensayo de captura de disulfuro dirigido al sitio para el cribado de fragmentos.
Se centró en la interacción dependiente de la fosforilación entre 14-3-3σ y un péptido derivado de ERα.
Mecanismos de estabilización determinados mediante el uso de la cristalografía de rayos X.

Principales resultados:

Estabilizadores ortostéricos identificados que aumentan la afinidad 14-3-3σ/ERα hasta 40 veces.
Elucidado el mecanismo de estabilización a través del análisis estructural.
Se ha demostrado una selectividad parcial de los fragmentos identificados para los motivos similares a ERα con respecto a otros clientes 14-3-3.

Conclusiones:

El enfoque de enlace es eficaz para descubrir estabilizadores de PPI.
Este estudio proporciona una base para el desarrollo de nuevas terapias dirigidas a los IPP en enfermedades como el cáncer de mama.
La estabilización del IPP representa una vía prometedora, aunque poco explorada, en el descubrimiento de fármacos.

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