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GPCR sintéticos para la detección y el control programables del comportamiento celular

Nicholas A Kalogriopoulos¹, Reika Tei¹, Yuqi Yan²

¹Department of Genetics, Stanford University, Stanford, CA, USA.

|December 5, 2024

Resumen

Los investigadores desarrollaron receptores de ingeniería acoplados a proteínas G (PAGER) programables que controlan las funciones celulares en respuesta a antígenos específicos. Esta herramienta de biología sintética ofrece modularidad y amplias aplicaciones en terapia e investigación.

Área de la Ciencia:

Biología sintética
Ingeniería molecular
Ingeniería celular

Sus antecedentes:

Los receptores sintéticos establecidos tienen limitaciones en la detección de antígenos solubles y carecen de control integrado de fármacos.
Los receptores de antígenos quiméricos están restringidos a antígenos inmovilizados y tienen un alcance de salida limitado.

Objetivo del estudio:

Diseñar nuevos receptores sintéticos acoplados a proteínas G (GPCR) para el control dependiente del antígeno de los procesos celulares.
Desarrollar una plataforma modular para receptores de ingeniería acoplados a proteínas G con puerta de antígeno programables (PAGER).

Principales métodos:

Escafios de GPCR diseñados con un dominio autoinhibidor condicional fusionado con los enlaces de nanobody.
Se ha logrado la entrada modular del antígeno donde la unión del antígeno alivia la autoinhibición, permitiendo la activación del receptor inducida por el fármaco.
PAGERs creados que responden a diversos antígenos solubles y de la superficie celular.

Principales resultados:

Se ha demostrado que los PAGER impulsan la expresión transgénica, la fluorescencia en tiempo real y la activación endógena de la proteína G.
Las aplicaciones exhibidas incluyen migración de células T, diferenciación de macrófagos, secreción de anticuerpos terapéuticos y control de la actividad neuronal.
Generó con éxito PAGER para más de una docena de antígenos biológicamente relevantes.

Conclusiones:

Los PAGER proporcionan una plataforma versátil y programable para el control celular específico del antígeno.
El diseño modular de los PAGER facilita una amplia utilidad en el descubrimiento de fármacos y la ciencia traslacional.
Esta tecnología permite la manipulación precisa de las funciones celulares a través de receptores sintéticos.

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