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El ADN circular y las moléculas híbridas ADN/ARN como andamios para el diseño de inhibidores de la ricina
Matthew B Sturm1, Setu Roday, Vern L Schramm
1Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Journal of the American Chemical Society
|April 10, 2007
Resumen
El ADN circular y los híbridos de ARN/ADN sirven como sustratos y andamios eficientes para la inhibición de la cadena A de la toxina ricina (RTA). Los nuevos inhibidores circulares logran la unión nanomolar, ofreciendo nuevas estrategias sintéticas para terapias dirigidas a RTA.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Sus antecedentes:
- La cadena A de toxina de ricina (RTA) es una potente proteína inactivadora de ribosomas que depurina el ARN ribosómico eucariota.
- El ARN mínimo y las estructuras de bucle del tallo del ADN son sustratos conocidos para la catálisis de RTA.
Objetivo del estudio:
- Explorar el ADN circular y los oligonucleótidos híbridos ADN / ARN como nuevos sustratos y andamios inhibidores para RTA.
- Desarrollar inhibidores de RTA altamente potentes utilizando arquitecturas moleculares no tradicionales.
Principales métodos:
- Síntesis y caracterización del ADN circular d(GAGA) y de los oligonucleótidos híbridos ADN/ARN cíclicos GdAGA.
- Ensayos enzimáticos para determinar los parámetros cinéticos (kcat/Km) de la RTA con nuevos sustratos.
- Diseño y síntesis de inhibidores analógicos del estado de transición que incorporan motivos circulares de GAGA.
Principales resultados:
- Los sustratos circulares d ((GAGA) exhibieron una actividad RTA significativamente mejorada (aumento de 92 veces en kcat / km) en comparación con las formas lineales.
- Los sustratos circulares demostraron tasas catalíticas comparables o superiores a las de los tradicionales sustratos de bucle de tallo.
- Un nuevo inhibidor circular, el ciclico G (((N-Bn) GA, logró una inhibición de unión apretada con un Ki de 70 nM, lo que representa el inhibidor de RTA más pequeño hasta la fecha.
Conclusiones:
- Los oligonucleótidos circulares representan sustratos y andamios mínimos efectivos para el diseño de inhibidores de RTA.
- El desarrollo de inhibidores pequeños y potentes basados en motivos circulares evita la necesidad de estructuras de bucle de tallo, abriendo nuevas vías sintéticas.
- Estos hallazgos allanan el camino para nuevas estrategias terapéuticas dirigidas a la toxicidad mediada por RTA.
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