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Diseño de moléculas de unión al ADN específicas de la secuencia para la inhibición de la metiltransferasa del ADN

JeenJoo S Kang¹, Jordan L Meier, Peter B Dervan

¹Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.

Journal of the American Chemical Society

|February 8, 2014

Resumen

Los investigadores desarrollaron nuevas moléculas pequeñas para atacar los sitios de CpG para el control de la metilación del ADN. Una molécula, hairpin 3, inhibe efectivamente la actividad de la metiltransferasa del ADN, ofreciendo una base para nuevas terapias epigenéticas.

Área de la Ciencia:

Biología Química Biología química.
La epigenética es la epigenética.
Biología Molecular Biología Molecular

Sus antecedentes:

Las díadas de CpG son elementos genómicos cruciales involucrados en la metilación del ADN y la regulación génica.
Las pequeñas moléculas dirigidas a las díadas de CpG son valiosas para modular la actividad transcripcional.
Los oligómeros de unión de ranura menor ofrecen una estrategia potencial para el reconocimiento de CpG específico de la secuencia.

Objetivo del estudio:

Para evaluar la eficacia de las poliamidas pirrole-imidazol de la horquilla del cabello en el reconocimiento de secuencias CpG.
Investigar la orientación de unión y la especificidad de estas poliamidas.
Establecer una base para el diseño de pequeñas moléculas que antagonizan la metilación de CpG.

Principales métodos:

Cribado de una biblioteca de pirrol-imidazol poliamidas de horquilla de pelo contra la secuencia 5'-CGCG-3'.
Utilizando la secuenciación de próxima generación para una evaluación imparcial de la especificidad de la secuencia.
Evaluar la inhibición de la actividad de la metiltransferasa del ADN por las poliamidas identificadas.

Principales resultados:

La poliamida PyImβIm-γ-PyImβIm de la horquilla (1) favoreció inesperadamente la unión 5'-GCGC-3' en una orientación inversa.
La modificación de PyImPyIm-γ-PyImβIm (3) restauró la preferencia 5'-CGCG-3' en una orientación hacia adelante.
Hairpin 3 demostró una inhibición superior de la actividad de la ADN metiltransferasa en comparación con la poliamida 1.

Conclusiones:

Las poliamidas de pirrol-imidazol se pueden diseñar para el reconocimiento específico de la secuencia CpG y la orientación de la unión.
La poliamida 3 de horquilla de pelo sirve como un potente inhibidor de la actividad de la ADN metiltransferasa en su sitio objetivo.
Estos hallazgos proporcionan un marco molecular para el desarrollo de antagonistas específicos de la secuencia de la metilación de CpG.

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