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La ingeniería O-GlcNAc de los agonistas de péptidos GPCR mejora su estabilidad y actividad in vivo
Paul M Levine, Aaron T Balana, Emmanuel Sturchler1
1Department of Molecular Medicine The Scripps Research Institute , Jupiter , Florida 33458 , United States.
Journal of the American Chemical Society
|August 17, 2019
Resumen
La O-GlcNAcilación mejora la estabilidad y la actividad in vivo de péptidos terapéuticos como GLP- 1 y PTH. Este nuevo enfoque supera la inestabilidad de los péptidos, ofreciendo una estrategia prometedora para desarrollar terapias mejoradas con péptidos.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Farmacología
Sus antecedentes:
- Las terapias con péptidos se enfrentan a desafíos con inestabilidad in vivo y vidas medias cortas.
- La glicosilación de proteínas mejora la estabilidad del suero, pero los métodos extracelulares son complejos.
- La O-GlcNAcilación, una glicosilación intracelular, inhibe la proteólisis de forma remota.
Objetivo del estudio:
- Investigar la aplicación de la O-GlcNAcilación para mejorar la estabilidad terapéutica del péptido.
- Diseñar análogos del péptido 1 parecido al glucagón (GLP-1) y la hormona paratiroidea (PTH) utilizando O-GlcNAcilación.
- Evaluar el impacto de la O-GlcNAcilación en la potencia, la estabilidad y la actividad in vivo de los péptidos.
Principales métodos:
- O-GlcNAcilación de los péptidos GLP-1 y PTH.
- Ensayos basados en células para evaluar la potencia del péptido y la activación del receptor.
- Ensayos de estabilidad sérica para medir la resistencia proteolítica.
- Estudios in vivo para evaluar las propiedades farmacocinéticas y farmacodinámicas.
- Modelado molecular basado en la estructura y mutagénesis de receptores.
Principales resultados:
- Los análogos O-GlcNAcilado de GLP- 1 y PTH fueron equipotentes a los péptidos nativos.
- Varios análogos de GLP-1 exhibieron agonismo sesgado.
- La O-GlcNAcilación mejoró significativamente la estabilidad sérica de ambos péptidos, incluso con sitios de modificación remotos.
- Los péptidos O-GlcNAcilados mostraron una mayor actividad in vivo.
- El modelado molecular proporcionó información sobre las interacciones de los receptores y la acomodación de O-GlcNAcilación.
Conclusiones:
- La O-GlcNAcilación es una estrategia viable para mejorar la estabilidad proteolítica de los péptidos terapéuticos.
- Este enfoque puede mejorar el rendimiento in vivo de péptidos como GLP-1 y PTH.
- La O-GlcNAcilación ofrece un método poderoso para diseñar terapias de péptidos con propiedades mejoradas.
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