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In vitro Cell Migration and Invasion Assays

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Un dímero de knottin químicamente entrelazado se une a las integrinas con afinidad picomolar e inhibe la migración y

Jun W Kim¹, Frank V Cochran, Jennifer R Cochran

¹Departments of †Bioengineering and ‡Chemical Engineering, Stanford University , Stanford, California 94305, United States.

Journal of the American Chemical Society

|December 9, 2014

Resumen

Los investigadores desarrollaron nuevos inhibidores de integrina dimérica utilizando la química del oximo, logrando una afinidad de unión significativamente mejorada a las células tumorales. Este enfoque es prometedor para el desarrollo de terapias más efectivas contra el cáncer dirigidas a la angiogénesis y las metástasis.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Descubrimiento de Drogas Descubrimiento de Drogas

Sus antecedentes:

Las integrinas alfa-v beta-3 (αvβ3), alfa-v beta-5 (αvβ5) y alfa-5 beta-1 (α5β1) son reguladores clave de la angiogénesis y las metástasis.
Los intentos anteriores de mejorar la eficacia del inhibidor de la integrina a través de la dimerización tuvieron un éxito limitado.

Objetivo del estudio:

Para sintetizar y caracterizar las miniproteínas de unión a la integrina diméricas (nottins) con una afinidad de unión mejorada.
Explorar la conjugación química basada en oximos para la creación de dímeros de nodos con variadas topologías moleculares.

Principales métodos:

Introducción de un aminoácido no natural que contiene aminooxy en los monómeros de la nottina.
Conjugación química de los monómeros de la nodina utilizando enlaces cruzados de dialdehído de diferentes longitudes.
Comparación de dímeros conjugados por oximo con dímeros fusionados genéticamente y un conocido inhibidor de la integrina (cilengitida).

Principales resultados:

Los dímeros de nodina conjugados con oximo exhibieron una afinidad de unión aparente significativamente mayor a las células tumorales en comparación con los monómeros.
La dimerización a través de un grupo aminoóxido cerca de la mitad de la proteína fue más efectiva que cerca del extremo C; la longitud del enlace cruzado no tuvo ningún impacto.
El dimero óptimo conjugado con oximo mostró un aumento de 150 veces en la afinidad de unión con respecto al monómero y superó a la cilengitida en la inhibición de la unión y la inhibición funcional.

Conclusiones:

La conjugación química basada en oximas es una estrategia crítica para crear inhibidores de integrina dimérica altamente potentes.
Los dimeros de knottin desarrollados demuestran una unión superior a las células tumorales y efectos anti-migración/proliferativos, lo que sugiere un potencial terapéutico.
Este enfoque ofrece una alternativa prometedora a los agentes de orientación de integrinas existentes para el tratamiento del cáncer.

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