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Diversificación de productos naturales utilizando un análogo de cofactor no natural de la S-adenosil-L-metionina

Changsheng Zhang¹, Rachel L Weller, Jon S Thorson

¹Laboratory for Biosynthetic Chemistry, University of Wisconsin National Cooperative Drug Discovery Group, Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222, USA.

Journal of the American Chemical Society

|March 2, 2006

Resumen

Los investigadores desarrollaron un nuevo cofactor sintético para las metiltransferasas, lo que permite la creación de diversas moléculas similares a fármacos. Este avance expande el uso de enzimas de productos naturales en el descubrimiento de fármacos mediante la utilización de cofactores no naturales.

Área de la Ciencia:

La bioquímica es la bioquímica.
Química orgánica es la química orgánica.
Descubrimiento de Drogas Descubrimiento de Drogas

Sus antecedentes:

Los análogos de adenosina con electrófilos específicos funcionan como agentes alquiladores del ADN dependientes de la metiltransferasa.
Las enzimas biosintéticas de productos naturales ofrecen potencial para generar nuevas estructuras moleculares.

Objetivo del estudio:

Introducir un nuevo cofactor sintético con un grupo 5'-aminoácido N-mostaza.
Para investigar la utilidad de este cofactor sintético con la rebeccamicina metiltransferasa (RebM).
Explorar el potencial de las metiltransferasas de productos naturales en el descubrimiento de fármacos utilizando cofactores no naturales.

Principales métodos:

Síntesis de un nuevo cofactor que lleva un colgante de 5'-aminoácido N-mostaza.
Reacciones enzimáticas que utilizan la rebecamicina metiltransferasa (RebM) y el cofactor sintético.
Caracterización de los análogos de rebecamicina generados.

Principales resultados:

El nuevo cofactor sintético fue utilizado de manera eficiente por RebM.
RebM generó una variedad de nuevos análogos de rebecamicina utilizando el cofactor sintético.
Esto representa la primera instancia de una metiltransferasa biológica, excluyendo las metiltransferasas del ADN, que emplea con éxito tales cofactores sintéticos.

Conclusiones:

Las metiltransferasas de productos naturales pueden ser diseñadas para aceptar cofactores no naturales.
Este enfoque mejora significativamente la diversidad molecular para el descubrimiento de medicamentos.
El estudio demuestra una nueva estrategia para generar análogos de productos naturales.

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