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Una estrategia quimioenzimática para la funcionalización selectiva del sitio de péptidos y proteínas nativas
Anna Fryszkowska1, Chihui An1, Oscar Alvizo2
1Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
Science (New York, N.Y.)
|June 16, 2022
Resumen
Las enzimas como las acilasas de penicilina G de ingeniería permiten una modificación precisa de la insulina nativa. Esta estrategia de bioconjugación mejora la síntesis de bioconjugados homogéneos para el desarrollo de fármacos.
Área de la Ciencia:
- Bioconjugación Química
- Ingeniería de proteínas
- Las modalidades terapéuticas
Sus antecedentes:
- La modificación selectiva del sitio de las biomoléculas es un reto debido a la complejidad y la reactividad similar de los grupos funcionales.
- El desarrollo de herramientas de síntesis eficientes es crucial para las nuevas modalidades terapéuticas.
Objetivo del estudio:
- Desarrollar una estrategia de bioconjugación altamente selectiva para la modificación de péptidos nativos.
- Diseñar enzimas para la manipulación programable de grupos funcionales en la insulina.
Principales métodos:
- Las acilasas de penicilina G diseñadas para lograr una modificación selectiva del sitio de la insulina.
- Las enzimas utilizadas para distinguir entre las fracciones amino en la insulina (N-terminales y lisina interna).
- Desarrolló un método para la manipulación programable de grupos de fenilacetamida que se pueden dividir.
Principales resultados:
- Se ha logrado una alta selectividad del sitio en la modificación de la insulina nativa utilizando enzimas de ingeniería.
- Bioconjugados homogéneos sintetizados con rendimiento y pureza mejorados en comparación con los métodos existentes.
- Demostró una estrategia para la funcionalidad programable de las proteínas nativas.
Conclusiones:
- La bioconjugación mediada por enzimas ofrece un enfoque poderoso para la modificación selectiva del sitio de la proteína.
- Esta estrategia permite la síntesis de bioconjugados homogéneos para aplicaciones terapéuticas.
- Abre nuevas vías para crear sondas biológicas y medicamentos a través de la funcionalización de proteínas.
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