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Un código genético reprogramado compacto para el descubrimiento de novo de tiopéptidos proteolíticamente estables
Alexander A Vinogradov1, Yue Zhang1, Keisuke Hamada2
1Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|March 16, 2024
Resumen
Este estudio introduce una plataforma de visualización de ARNm reprogramada para descubrir tiopéptidos metabólicamente estables. El nuevo método utiliza aminoácidos no proteinogénicos, lo que conduce a un mayor potencial de descubrimiento de fármacos.
Área de la Ciencia:
- La bioquímica
- Productos naturales Química
- Descubrimiento de drogas
Sus antecedentes:
- Los tiopéptidos son productos naturales complejos con potencial de bioingeniería.
- Las plataformas de descubrimiento de tiopéptidos existentes producen compuestos metabólicamente inestables debido al uso de aminoácidos proteinogénicos.
Objetivo del estudio:
- Desarrollar una plataforma de visualización de tiopéptidos/ARNm para el descubrimiento de tiopéptidos metabólicamente estables.
- Incorporar aminoácidos no proteinogénicos en las estructuras tiopéptidas para una mayor estabilidad.
Principales métodos:
- Utilizó códigos genéticos reprogramados compactos en las bibliotecas de visualización de ARNm.
- Se realizaron selecciones de afinidad contra la cinasa que interactúa con Traf2 y NCK (TNIK).
- Se determinó la afinidad tiopéptida (K_D) y la actividad inhibidora de la quinasa (IC_50).
Principales resultados:
- Tiopéptidos descubiertos compuestos predominantemente por elementos estructurales no proteinogénicos.
- Se identificaron aglutinantes de alta afinidad a TNIK (mejor K_D = 2,1 nM) con actividad inhibidora de la quinasa (mejor IC_50 = 0,15 μM).
- Se alcanza una alta estabilidad metabólica en suero humano (vida media de hasta 99 h) con hasta 15 aminoácidos no proteinogénicos.
Conclusiones:
- La plataforma reprogramada permite el descubrimiento de tiopéptidos con una estabilidad metabólica significativamente mejorada.
- Los bloques de construcción no proteinogénicos facilitan el compromiso del objetivo y las conformaciones de plegado únicas.
- Este avance es crucial para las primeras aplicaciones de descubrimiento de fármacos que requieren candidatos terapéuticos estables.
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