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Antagonismo alostero intracelular del receptor CCR9

Christine Oswald¹, Mathieu Rappas¹, James Kean¹

¹Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK.

|December 8, 2016

Resumen

La estructura cristalina del receptor de quimiocinas CC tipo 9 (CCR9) unido al vercirnón revela un mecanismo de antagonismo alostérico. Este hallazgo explica los problemas anteriores de eficacia de los fármacos y ofrece nuevos objetivos para el diseño de fármacos receptores de quimiocinas.

Área de la Ciencia:

La bioquímica
Inmunología
Biología estructural

Sus antecedentes:

Las quimiocinas y los receptores acoplados a proteínas G (GPCR) son cruciales en las respuestas inmunes y las enfermedades, lo que las convierte en objetivos farmacológicos clave.
A pesar de los numerosos candidatos clínicos, solo se aprueban dos medicamentos dirigidos a las quimiocinas, lo que pone de relieve los desafíos en el desarrollo de medicamentos y la comprensión de los mecanismos.
El receptor de quimiocinas CC tipo 9 (CCR9) es un objetivo para la enfermedad inflamatoria intestinal, pero su antagonista vercirnón mostró una eficacia limitada en los ensayos.

Objetivo del estudio:

Aclarar la base estructural para el antagonismo del receptor de quimiocinas CC tipo 9 (CCR9) por el vercirnón.
Comprender el mecanismo de acción de vercirnon e informar el diseño futuro de fármacos para CCR9 y los receptores quimiocinos relacionados.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar la estructura del receptor CCR9 en complejo con vercirnón a una resolución de 2,8 Å.

Principales resultados:

La estructura cristalina reveló que el vercirnón se une al lado intracelular del receptor CCR9.
Este sitio de unión media el antagonismo alostérico al prevenir el acoplamiento de la proteína G, lo que explica la necesidad de dosis altas de antagonista.
Los hallazgos identifican un nuevo sitio de unión alostérico en un GPCR, aplicable a CCR9 y otros receptores quimiocinos.

Conclusiones:

Vercirnon actúa como un antagonista alostérico de CCR9 al unirse a su cara intracelular e inhibir el acoplamiento de la proteína G.
El sitio de unión identificado proporciona una justificación para las propiedades del fármaco y sugiere una nueva estrategia para dirigirse a los GPCR, incluidos los receptores quimiocinos.
Esta visión estructural abre caminos para diseñar fármacos más efectivos dirigidos a los receptores quimiocinos para diversas enfermedades.

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