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Diseño racional de inhibidores selectivos de moléculas pequeñas para las interacciones proteína-proteína de la
Logan R Hoggard1, Yongqiang Zhang1, Min Zhang1
1Department of Chemistry, Center for Cell and Genome Science, University of Utah , Salt Lake City, Utah 84112-0850, United States.
Journal of the American Chemical Society
|September 10, 2015
Resumen
Los investigadores diseñaron pequeñas moléculas orgánicas para inhibir selectivamente las interacciones proteína-proteína de la hélice alfa (IPP). Estos nuevos inhibidores se dirigen a las interacciones beta-catenina/BCL9, ofreciendo potencial para terapias contra el cáncer.
Área de la Ciencia:
- Química medicinal
- Biología Química
- Biología molecular
Sus antecedentes:
- Las interacciones proteína-proteína mediadas por la hélice alfa (IPP) son cruciales en los procesos biológicos.
- Dirigirse a estos IBP con moléculas pequeñas ofrece un potencial terapéutico.
- La comprensión de las interacciones de puntos calientes es clave para el diseño de inhibidores selectivos.
Objetivo del estudio:
- Diseñar y sintetizar pequeñas moléculas orgánicas que inhiban selectivamente los IBP mediados por la hélice alfa.
- Desarrollar inhibidores dirigidos al IBP de la beta-catenina/BCL9 en lugar del IBP de la beta-catenina/cadherina.
- Explorar el potencial terapéutico de estos inhibidores en los cánceres dependientes de Wnt/beta-catenina.
Principales métodos:
- Minería de datos del Banco de datos de proteínas utilizando la base de datos HippDB para identificar las características de los puntos calientes.
- Diseño de un andamio genérico que imita la unión de puntos calientes de la hélice alfa.
- Síntesis y caracterización de inhibidores de moléculas pequeñas.
- Estudios de mutagenesis dirigidos al sitio y relación estructura-actividad (SAR) para determinar los modos de unión.
Principales resultados:
- Se diseñó un nuevo andamio genérico basado en el análisis de puntos calientes.
- Se sintetizó una serie de inhibidores de moléculas pequeñas selectivos para los IBP de la beta-catenina/BCL9.
- Se demostró que los inhibidores interrumpen selectivamente las interacciones beta-catenina/BCL9 en comparación con la beta-catenina/cadherina.
- Los inhibidores suprimían la señalización de Wnt, regulaban a la baja los genes objetivo e inhibían el crecimiento de las células cancerosas.
Conclusiones:
- La inhibición selectiva de los IBP de hélice alfa es posible con moléculas orgánicas pequeñas.
- Los inhibidores diseñados ofrecen una nueva estrategia para dirigir la señalización de Wnt/beta-catenina.
- Estos hallazgos allanan el camino para el desarrollo de nuevas terapias para cánceres relevantes.
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