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Mejora mediada por prolina en la evolutividad de péptidos ricos en disulfuro para el descubrimiento de enlaces de

Hongtan Liu¹, Lulu Song^2,3, Xiaoting Meng^4,5

¹The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

Journal of the American Chemical Society

|July 2, 2025

Resumen

Desarrollamos una estrategia de exploración de prolina para mejorar la evolutividad de los péptidos ricos en disulfuro (DRP), lo que permite el descubrimiento de agentes terapéuticos potentes dirigidos a TROP2 y 4-1BB con perfiles de seguridad mejorados.

Área de la Ciencia:

Bioquímica y Biología Molecular
Descubrimiento y desarrollo de fármacos
Ingeniería de proteínas

Sus antecedentes:

Los péptidos ricos en disulfuro (DRP), especialmente los motivos del nudo de cistina inhibidor (ICK), ofrecen estabilidad y especificidad para el desarrollo terapéutico.
La plasticidad estructural limitada de los DRP dificulta la ingeniería de nuevas funciones, lo que representa un cuello de botella para el descubrimiento de fármacos.

Objetivo del estudio:

Desarrollar una nueva estrategia de exploración de prolina para mejorar la evolución de los andamios ICK.
Diseñar variantes de DRP con mejor capacidad de plegado y tolerancia de secuencia para la construcción de bibliotecas.
Identificar y caracterizar nuevos DRP con potencial terapéutico contra objetivos de cáncer.

Principales métodos:

Implementó una estrategia de escaneo de prolina para diseñar andamios ICK.
Construyó diversas bibliotecas de péptidos utilizando plataformas de visualización de ARNm y fagos.
Se realizó la caracterización estructural y se evaluó el potencial terapéutico de los DRP evolucionados, incluida una terapia de células T CAR basada en DRP.

Principales resultados:

Variantes de ICK diseñadas con mayor plegabilidad y tolerancia a las variaciones de secuencia.
DRP identificados con baja afinidad nanomolar para TROP2 y 4-1BB.
Desarrolló una terapia de células T CAR basada en DRP que demuestra una potencia comparable y una seguridad mejorada en comparación con las células T CAR basadas en scFv.

Conclusiones:

La estrategia de escaneo de prolina mejora significativamente la evolución de la DRP, superando las limitaciones anteriores.
Los DRP evolucionados exhiben estructuras únicas, alta eficiencia de plegamiento oxidativo y potencial terapéutico.
Este marco facilita el descubrimiento de diversos DRP para amplias aplicaciones terapéuticas.

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