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Degradación selectiva de proteínas multiméricas mediante pegamento molecular basado en TRIM21 y degradantes PROTAC
Panrui Lu1, Yalong Cheng2, Lei Xue1
1Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China; National Institute of Biological Sciences, Beijing 102206, China.
Cell
|November 2, 2024
Resumen
Un nuevo pegamento molecular, (S) -ACE-OH, se dirige a TRIM21 para degradar las proteínas de los poros nucleares. Este enfoque permite la degradación selectiva de conjuntos de proteínas asociadas a enfermedades, ofreciendo nuevas estrategias terapéuticas para diversas afecciones.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- La degradación proteica dirigida (TPD) utiliza pegamentos moleculares o PROTAC para eliminar las proteínas de la enfermedad a través de las ligasas de ubiquitina E3.
- Los métodos TPD existentes están limitados por una selección estrecha de ligasas E3.
Objetivo del estudio:
- Para explorar nuevos pegamentos moleculares para la degradación de proteínas dirigidas.
- Investigar el potencial del metabolito de la acepromazina (S) -ACE-OH en la enfermedad de Parkinson.
- Desarrollar agentes degradantes multimerselectivos para conjuntos de proteínas asociados a enfermedades.
Principales métodos:
- Se identificó (S) -ACE-OH como un pegamento molecular que induce la interacción de TRIM21 y NUP98.
- Se han desarrollado PROTAC basados en acepromazina para la degradación proteica dirigida.
- Se ha evaluado la selectividad de degradación de las proteínas multiméricas frente a las monoméricas.
Principales resultados:
- (S) -ACE-OH indujo la degradación mediada por TRIM21 de las proteínas de los poros nucleares, interrumpiendo el transporte nucleocitoplasmático.
- Los PROTAC basados en acepromazina degradan selectivamente las proteínas multiméricas, incluidas las de los condensados biomoleculares.
- La activación de TRIM21 se relacionó con el agrupamiento inducido por el sustrato, lo que explica la selectividad de la degradación.
Conclusiones:
- Los pegamentos moleculares basados en TRIM21 y los PROTAC ofrecen una nueva estrategia de TPD.
- Se puede lograr la degradación multimer-selectiva, dirigida a los conjuntos de proteínas que causan enfermedades.
- Este enfoque es prometedor para el tratamiento de enfermedades autoinmunes, neurodegeneración y cáncer.
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