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Ligandos de moléculas pequeñas dirigidos a receptores de transporte de lisosomas y el paisaje emergente de quimeras

Jingjing Yang¹, Heping Zhu²

¹Department of Pharmacy, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing 312000, China.

Journal of medicinal chemistry

|September 1, 2025

Resumen

Las quimeras dirigidas a lisosomas (LYTAC) ofrecen un nuevo método para la degradación de proteínas dirigidas de proteínas extracelulares. Los LYTAC de molécula pequeña son prometedores para mejorar la administración de medicamentos y las aplicaciones terapéuticas.

Área de la Ciencia:

La bioquímica
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Las estrategias de degradación proteica dirigida (TPD) se dirigen principalmente a las proteínas intracelulares.
Las proteínas extracelulares son difíciles de degradar utilizando métodos dependientes del proteasoma.
Las quimeras que se dirigen a los lisosomas (LYTAC) permiten la degradación de las proteínas extracelulares al secuestrar las vías lisosómicas.

Objetivo del estudio:

Revisar los ligandos de pequeñas moléculas y péptidos para los LYTAC.
Para analizar los LYTAC dirigidos a varios receptores de transporte de lisosomas.
Explorar nuevas vías endocíticas para el desarrollo de LYTAC.

Principales métodos:

Examen de ligandos de pequeñas moléculas y péptidos para LYTAC.
Análisis de las características estructurales y los mecanismos de unión.
Investigación de las vías endocíticas no canónicas para aplicaciones de LYTAC.

Principales resultados:

Los LYTAC de molécula pequeña muestran una farmacocinética, una penetración en los tejidos y una síntesis superiores en comparación con los conjugados macromoleculares.
Los LYTAC pueden desarrollarse utilizando diversos receptores, incluidos los GPCR, las integrinas y los portadores de soluto.
Las estrategias emergentes explotan vías endocíticas no canónicas para mejorar la eficacia de LYTAC.

Conclusiones:

Se propone un marco para el diseño racional de LYTAC, centrado en la ingeniería de ligandos y la selección de receptores.
La optimización de la especificidad, la eficacia y el potencial de traducción de LYTAC requiere abordar desafíos clave.
Los LYTAC representan una modalidad terapéutica prometedora para la degradación de las proteínas extracelulares.

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