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Identificación de activadores de moléculas pequeñas de criptocromo

Tsuyoshi Hirota¹, Jae Wook Lee, Peter C St John

¹Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.

Science (New York, N.Y.)

|July 17, 2012

Resumen

Un nuevo compuesto, KL001, estabiliza las proteínas criptocromo (CRY), alargando el período circadiano. Este descubrimiento ofrece una estrategia terapéutica potencial para las enfermedades metabólicas como la diabetes al atacar el reloj interno del cuerpo.

Área de la Ciencia:

Cronobiología cronobiología.
Farmacología Molecular Farmacología Molecular
Investigación de Enfermedades Metabólicas.

Sus antecedentes:

La interrupción del reloj circadiano está relacionada con trastornos metabólicos.
Dirigirse a las proteínas del reloj central con pequeñas moléculas es una vía terapéutica prometedora.
Pocos compuestos se dirigen selectivamente a las proteínas clave del reloj como el criptocromo (CRY).

Objetivo del estudio:

Identificar nuevas moléculas pequeñas que modulan la función del reloj circadiano.
Para investigar el mecanismo de acción y los efectos fisiológicos de un compuesto recién identificado, KL001.1.
Explorar el potencial terapéutico de la orientación de CRY para enfermedades metabólicas como la diabetes.

Principales métodos:

Se realizó una pantalla fenotípica circadiana basada en células no sesgada para identificar moduladores.
Utilizó KL001 para estudiar la estabilidad de la proteína criptocromo (CRY) y la longitud del período circadiano.
Empleó modelos matemáticos para analizar las funciones funcionales de CRY1 y CRY2.
Se evaluó el impacto de KL001 en la gluconeogénesis inducida por glucagón en hepatocitos primarios.

Principales resultados:

Identificó KL001, una pequeña molécula que interactúa específicamente con el criptocromo (CRY).
KL001 previene la degradación dependiente de la ubiquitina de CRY, lo que lleva a un período circadiano alargado.
Se descubrió que CRY1 y CRY2 tienen funciones similares en la regulación del período circadiano.
La estabilización de CRY mediada por KL001 inhibió la gluconeogénesis inducida por glucagón en hepatocitos.

Conclusiones:

KL001 sirve como una herramienta valiosa para estudiar la fisiología regulada por CRY.
Estabilizar la CRY ofrece un mecanismo potencial para el desarrollo de terapias basadas en el reloj para la diabetes.
La orientación del reloj circadiano a través de la modulación CRY es prometedora para el tratamiento de enfermedades metabólicas.

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