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Diseño y biosíntesis de Alboflavusinas diméricas con enlaces de Biaryl a través del acoplamiento de enlaces C-C
Zhengyan Guo1, Pengwei Li1, Guozhu Chen2
1State Key Laboratory of Microbial Resources , Institute of Microbiology, Chinese Academy of Sciences , Beijing 100101 , China.
Journal of the American Chemical Society
|December 6, 2018
Resumen
Los investigadores diseñaron nuevas alboflavusinas diméricas (di-AFN) de Streptomyces alboflavus. Estos di-AFN exhiben propiedades antibacterianas y antitumorales mejoradas en comparación con sus contrapartes monoméricas, mostrando una estrategia prometedora para el descubrimiento de fármacos de productos naturales.
Área de la Ciencia:
- Química de los productos naturales
- Biología sintética
- Biotecnología microbiana
Sus antecedentes:
- Las Alboflavusinas (AFN) son ciclohexapéptidos de Streptomyces alboflavus con moderada actividad antibacteriana y antitumoral.
- La biosíntesis de AFN involucra una maquinaria de sintetasa de péptidos no ribosómica, con un precursor clave de 6-cloro-L-triptófano suministrado por un gen de triptófano halogenasa externo.
- Las relaciones estructura-actividad de los compuestos similares a AFN guiaron el diseño de nuevos derivados.
Objetivo del estudio:
- Diseñar y generar alboflavusinas diméricas (di-AFN) con enlaces biaílicos regiospecíficos.
- Evaluar las actividades antibacterianas y antitumorales mejoradas de los di-AFN en comparación con sus formas monoméricas.
- Demostrar una estrategia racional para mejorar la bioactividad de los productos naturales mediante la ingeniería biotecnológica.
Principales métodos:
- Generación biotecnológica de di-AFN mediante la expresión de genes P450 (hmtS o clpS) en cepas de Streptomyces alboflavus (tipo salvaje y mutante).
- Diseño de di-AFN basado en el conocimiento de la relación estructura-actividad de los ciclohexapéptidos relacionados.
- Evaluación in vitro e in vivo de las actividades antibacterianas y antitumorales de los di-AFN generados.
Principales resultados:
- Se diseñaron y generaron con éxito dos AFN diméricos (di-AFN) con enlaces biarálicos regiospecíficos.
- Los di-AFN generados exhibieron actividades antibacterianas y antitumorales significativamente mejoradas en comparación con sus contrapartes monoméricas.
- El estudio validó la eficacia del diseño racional y el enfoque biotecnológico para mejorar la eficacia del producto natural.
Conclusiones:
- La producción biotecnológica de di-AFN representa una estrategia exitosa para generar nuevos congéneres de productos naturales.
- Los di-AFN diseñados muestran una bioactividad superior, ofreciendo potencial para el desarrollo de nuevos agentes terapéuticos.
- Este trabajo ejemplifica un enfoque racional para el descubrimiento y la optimización de medicamentos de productos naturales.
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