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N-terminal protein-macrocycles habilitados por reacciones de cascada de adición/expansión de anillo conjugadas
Owen R Hughes1,2, Afzaal Tufail1,2,3, Esme Hutton1,2,3
1Department of Chemistry, University of York York YO10 5DD UK martin.fascione@york.ac.uk chris.spicer@york.ac.uk william.unsworth@york.ac.uk.
Chemical science
|December 24, 2025
Resumen
Desarrollamos un nuevo método de modificación de proteínas utilizando acriloylimidas para la bioconjugación N-terminal. Esta reacción de adición/expansión de anillo conjugada (CARE) crea conjugados estables de proteína-macrociclo para la investigación biológica y la terapéutica.
Área de la Ciencia:
- Biología Química
- Biomedicina
- Ingeniería de Proteínas
Sus antecedentes:
- La modificación química de proteínas es crucial para los avances en biología química, biología celular y biomedicina.
- Los métodos existentes pueden carecer de selectividad o estabilidad en la conjugación de proteínas.
Objetivo del estudio:
- Introducir un método novedoso y eficiente para la bioconjugación de proteínas N-terminal.
- Crear conjugados estables de proteína-macrociclo utilizando una reacción en cascada única.
Principales métodos:
- Se utilizaron acriloylimidas simples y fáciles de preparar como reactivos.
- Se emplearon reacciones en cascada de adición/expansión de anillo conjugadas (CARE) para la modificación de proteínas.
- Se demostró la diversificación de macrociclos de proteínas en etapa tardía.
Principales resultados:
- Se logró una alta selectividad N-terminal en la bioconjugación de proteínas.
- Se formaron conjugados estables de proteína-macrociclo a través de la expansión de anillo irreversible.
- Se aplicó con éxito el método a la obtención de imágenes de cáncer basadas en nanobodies y a la modulación de la interacción del receptor de quimiocinas.
- Se desacopló la endocitosis del receptor acoplado a proteína G (GPCR) de la fosforilación.
Conclusiones:
- La plataforma de bioconjugación CARE es potente y versátil para crear conjugados de proteínas novedosos.
- Este método permite la construcción de herramientas para diseccionar mecanismos biológicos.
- Ofrece potencial para el desarrollo de nuevas modalidades terapéuticas.
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