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Beclin 1-ATG14L Inhibidor de la interacción proteína-proteína Inhibe selectivamente la autofagia a través de la

Ivan Pavlinov¹, Maryna Salkovski¹, Leslie N Aldrich¹

¹Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago Illinois 60607, United States.

Journal of the American Chemical Society

|April 23, 2020

Resumen

Los investigadores desarrollaron un nuevo método para atacar específicamente la autofagia de las células cancerosas al interrumpir una interacción proteica clave. Este enfoque inhibe el crecimiento tumoral y la resistencia a la quimioterapia sin afectar los procesos celulares esenciales.

Área de la Ciencia:

La bioquímica
Biología celular
Investigación del cáncer

Sus antecedentes:

La autofagia es un proceso de reciclaje celular vital para la supervivencia de las células cancerosas, proporcionando nutrientes a los tumores y protegiendo contra la quimioterapia.
Las estrategias actuales dirigidas a la autofagia, como la inhibición de la quinasa, carecen de especificidad, afectando las funciones celulares esenciales.
La lipidquinasa VPS34 está involucrada en dos complejos: el Complejo I para la formación de autofagosomas y el Complejo II para el tráfico endosómico.

Objetivo del estudio:

Desarrollar un inhibidor específico de la autofagia dirigido a la interacción proteína-proteína de Beclin 1-ATG14L.
Para crear un ensayo de alto rendimiento para detectar moléculas que interrumpan esta interacción.
Validar la especificidad y eficacia de los compuestos identificados en la inhibición de la autofagia sin afectar el tráfico de vesículas.

Principales métodos:

Desarrolló un ensayo celular NanoBRET para medir la interacción Beclin 1-ATG14L.
Se examinaron 2560 moléculas pequeñas utilizando el ensayo NanoBRET.
Se validó el efecto de un compuesto de plomo en la formación del complejo I de VPS34, la inhibición de la autofagia y el tráfico de vesículas mediante la evaluación de la interacción Beclin-UVRAG.

Principales resultados:

Se identificaron 19 moléculas que interrumpieron la interacción Beclin 1-ATG14L.
Se confirmó que una molécula inhibió la formación del Complejo I de VPS34 y la autofagia.
Se demostró que esta molécula no interrumpe la interacción Beclin-UVRAG, preservando el tráfico de vesículas.

Conclusiones:

Dirigirse a la interacción proteína-proteína Beclin 1-ATG14L es una estrategia viable para la inhibición selectiva de la autofagia.
Se identificó una nueva molécula que inhibe específicamente la autofagia, ofreciendo una herramienta terapéutica potencial.
Este descubrimiento abre caminos para desarrollar moduladores específicos de la autofagia para la terapia y la investigación del cáncer.

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