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Evolución dirigida de grupos de carbohidratos 2'-modificados por fluoro, apoyados por ARN que se unen fuertemente al
Richard L Redman1, Isaac J Krauss1
1Department of Chemistry, Brandeis University, 415 South Street MS 015, Waltham, Massachusetts 02454, United States.
Journal of the American Chemical Society
|June 7, 2021
Resumen
Desarrollamos un nuevo método usando la evolución dirigida para crear ligandos de carbohidratos multivalentes. Esta plataforma diseña grupos óptimos de glicanos para la unión de alta afinidad, demostrada por la orientación de anticuerpos contra el VIH.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- Descubrimiento de drogas
Sus antecedentes:
- Las proteínas de unión a los carbohidratos (CBPs) son cruciales en los procesos biológicos y las enfermedades.
- Las interacciones de alta afinidad a menudo dependen de la multivalencia, donde múltiples glicanos se unen a una proteína.
- El desarrollo de terapias efectivas basadas en carbohidratos requiere un control preciso de la presentación de glicano.
Objetivo del estudio:
- Establecer una nueva plataforma para el diseño de ligandos multivalentes de grupos de carbohidratos.
- Para utilizar la evolución dirigida para optimizar el agrupamiento de glicanos en una columna vertebral estable.
- Validar la plataforma seleccionando ligandos dirigidos a un anticuerpo ampliamente neutralizante específico.
Principales métodos:
- Empleando la evolución dirigida para seleccionar secuencias de ARN funcionales.
- Diseño de columnas vertebrales de ARN 2'-fluoro modificado estable en suero para presentar glicanos.
- Evaluación de un gran grupo de secuencias (∼10^13) para aglutinantes de alta afinidad.
Principales resultados:
- Se seleccionaron con éxito grupos de glicanos de oligomanosa (Man9) con alta afinidad para el anticuerpo 2G12 del VIH.
- Afinidades de unión alcanzadas en el rango de 13 a 36 nM.
- Demostró la eficacia de la plataforma de ARN-F en la creación de potentes ligandos multivalentes.
Conclusiones:
- La plataforma de evolución dirigida permite el diseño racional de ligandos de carbohidratos multivalentes.
- Este enfoque es eficaz para desarrollar enlaces de alta afinidad contra objetivos difíciles como los anticuerpos ampliamente neutralizantes.
- La columna vertebral del ARN-F ofrece estabilidad y presentación óptima para los grupos de glicanos en aplicaciones terapéuticas.
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