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Modulación química seleccionada por la quiralidad de la agregación amiloide

Nan Gao¹, Zhi Du^1,2, Yijia Guan^1,2

¹Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization , Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun , Jilin 130022 , China.

Journal of the American Chemical Society

|April 11, 2019

Resumen

Los derivados de polioxometalato de quiral inhiben eficazmente la agregación de péptidos β-amiloides. Los POM modificados con fenilalanina, en particular el enantiómero d, muestran una enantioselectividad significativa y un potencial terapéutico para los modelos de la enfermedad de Alzheimer.

Área de la Ciencia:

La bioquímica
Ciencias de los materiales
La neurociencia

Sus antecedentes:

La agregación del péptido β-amiloide (Aβ) es fundamental para la patogénesis de la enfermedad de Alzheimer.
La agregación de Aβ está influenciada por los entornos quirales y exhibe una quiralidad inherente.
La orientación de la agregación Aβ requiere estrategias que consideren la estereoselectividad.

Objetivo del estudio:

Para sintetizar derivados quirales de polioxometalato modificados por aminoácidos (POM).
Investigar el efecto de estos POM en la agregación de Aβ.
Evaluar el potencial terapéutico de las POM enantioselectivas en modelos de la enfermedad de Alzheimer.

Principales métodos:

Síntesis de los POM modificados por los aminoácidos d y l (His, Glu, Leu, Phe).
Ensayos biofísicos y espectrales (fluorescencia, CD, RMN, simulaciones de MD, ITC) para evaluar la inhibición de la agregación de Aβ.
Estudios in vivo con C. elegans transgénico de la enfermedad de Alzheimer (estirpe CL2006).

Principales resultados:

Los POM modificados con fenilalanina mostraron una inhibición superior de la agregación de Aβ en comparación con otros derivados de aminoácidos.
La POM modificada por d-Phe mostró una inhibición 8 veces mayor que la POM modificada por l-Phe, demostrando una alta enantioselectividad.
Los estudios in vivo confirmaron la penetración de la barrera hematoencefálica, la extensión de la vida útil en modelos de EA y una baja citotoxicidad.

Conclusiones:

Los POM quirales, especialmente el d-Phe-POM, son inhibidores potentes y enantioselectivos de la agregación de Aβ.
Estos hallazgos resaltan el potencial de las POM quirales como agentes terapéuticos para la enfermedad de Alzheimer.
El estudio subraya la importancia de la quiralidad en el diseño de inhibidores eficaces de la agregación de Aβ.

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