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Foldameros α/β-peptídicos dirigidos a las interacciones intracelulares entre proteínas con actividad en células vivas

James W Checco, Erinna F Lee^1,2, Marco Evangelista¹

¹The Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria 3052, Australia.

Journal of the American Chemical Society

|August 29, 2015

Resumen

Los péptidos modificados que combinan aminoácidos alfa y beta muestran una mayor estabilidad y penetración celular. Estos nuevos péptidos alfa/beta inhiben efectivamente las interacciones proteicas involucradas en la apoptosis, ofreciendo un potencial terapéutico mejorado.

Área de la Ciencia:

La bioquímica
Biología molecular
Descubrimiento de drogas

Sus antecedentes:

Los péptidos convencionales se enfrentan a limitaciones in vivo, incluidas las vidas medias cortas debido a la degradación proteolítica y la escasa permeabilidad de la membrana celular.
Estas limitaciones impiden el desarrollo de péptidos como antagonistas efectivos de las interacciones proteína-proteína para aplicaciones terapéuticas.

Objetivo del estudio:

Ampliar el enfoque alfa/beta para las interacciones proteína-proteína intracelulares.
Diseñar y evaluar un péptido alfa/beta grapado basado en el péptido alfa Bim BH3.

Principales métodos:

Generación de péptidos alfa/beta que incorporan residuos de aminoácidos alfa y beta.
Diseño de un péptido alfa/beta "agrapado" con un enlace cruzado de hidrocarburos para mejorar la estabilidad de la hélice alfa.
Evaluación de la permeabilidad celular, la resistencia proteolítica y la imitación funcional del péptido alfa primario.

Principales resultados:

El péptido alfa/beta grapado imitó con éxito la estructura y función del péptido alfa grapado padre.
El péptido alfa/beta demostró la capacidad de entrar en tipos celulares específicos e inhibir las interacciones proteína-proteína en la señalización apoptótica.
El péptido alfa/beta exhibió una resistencia aproximadamente 100 veces mayor a la proteólisis en comparación con el péptido alfa original.

Conclusiones:

La modificación de la columna vertebral a través del diseño de péptido alfa / beta ofrece beneficios sinérgicos cuando se combina con modificaciones periféricas como el enlace cruzado de la cadena lateral.
Los péptidos alfa/beta representan una estrategia prometedora para el desarrollo de péptidos terapéuticos más estables y que penetran en las células.
Este enfoque mejora el potencial de la ingeniería de péptidos para aplicaciones biomédicas, particularmente en la orientación de procesos intracelulares.

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