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Moléculas bifuncionales que inducen la degradación dirigida y la transcitosis de las proteínas extracelulares en las

Rebecca A Howell¹, Shikun Wang¹, Mihir Khambete¹

¹Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States.

Journal of the American Chemical Society

|June 10, 2024

Resumen

Las nuevas moléculas de TransMoDEs pueden atravesar la barrera hematoencefálica para degradar las proteínas objetivo en el sistema nervioso central. Este enfoque de degradación proteica dirigida (TPD) ofrece una nueva estrategia terapéutica para las enfermedades neurológicas.

Área de la Ciencia:

La neurociencia
La bioquímica
Descubrimiento de drogas

Sus antecedentes:

La degradación proteica dirigida (DPT) es una estrategia terapéutica prometedora.
La barrera hematoencefálica (BBB) restringe el suministro de fármacos al sistema nervioso central (SNC).

Objetivo del estudio:

Desarrollar una nueva clase de moléculas pequeñas bifuncionales, los TransMoDEs (degradadores moleculares de proteínas extracelulares que inducen la transcitosis).
Permitir la degradación de las proteínas objetivo dentro del SNC facilitando la transcitosis a través de la BBB.

Principales métodos:

Los TransMoDEs fueron diseñados utilizando el péptido Angiopep-2 para la transcitosis BBB.
Se incorporaron ligandos de biotina o cloroalcano para el reclutamiento de proteínas diana (estreptavidina o HaloTag).
Los experimentos se llevaron a cabo utilizando un modelo bEnd.3 BBB para evaluar los mecanismos de endocitosis, localización lisosómica y transcitosis.

Principales resultados:

TransMoDEs desencadenó con éxito la endocitosis y la degradación de las proteínas objetivo (estreptavidina, HaloTag).
La absorción objetivo se observó a través de una vía de endocitosis mediada por clatrina.
Se demostró la transcitosis de las proteínas objetivo a través del modelo BBB.
La proteína 1 relacionada con el receptor de lipoproteínas de baja densidad (LRP1) no fue requerida exclusivamente para la absorción mediada por Angiopep-2.

Conclusiones:

Los TransMoDEs pueden reclutar, transcitar y degradar proteínas extracelulares dentro de las células relevantes del SNC.
Esta tecnología tiene potencial para desarrollar nuevas terapias dirigidas a enfermedades neurodegenerativas mediante la eliminación de proteínas patógenas.

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