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Síntesis Química Total de una Glicosulina Humana No Fibrillada

Mohammed Akhter Hossain, Ryo Okamoto¹, John A Karas

¹Graduate School of Science , Osaka University , Toyonaka , Osaka 560-0043 Japan.

Journal of the American Chemical Society

|December 19, 2019

Resumen

Este estudio introduce un nuevo método de glucosilación química para la insulina, creando una glucosulina estable y no fibrilante. Esta formulación mejorada de insulina muestra potencial terapéutico para el tratamiento de la diabetes, especialmente en bombas de insulina.

Área de la Ciencia:

La bioquímica
Desarrollo de drogas
Endocrinología

Sus antecedentes:

La terapia con insulina es crucial para el manejo de la diabetes, pero está limitada por la formación de fibrillas, lo que afecta la estabilidad y la administración del medicamento.
La glicosilación se explora como una estrategia para mejorar la estabilidad de las proteínas y el valor terapéutico.
Los métodos de glicosilación enzimática existentes producen productos heterogéneos, lo que requiere enfoques mejorados.

Objetivo del estudio:

Desarrollar una nueva estrategia química para la producción de insulina glicosilada homogénea (glicosulina).
Evaluar el potencial terapéutico de la disialo-glicosulina sintetizada, centrándose en la estabilidad, la unión al receptor y la eficacia.
Para evaluar la propensión a la formación de fibrillas del análogo de insulina modificado.

Principales métodos:

Se empleó una estrategia química novedosa para sintetizar la disialo-glucosulina homogénea.
Se utilizaron ensayos in vitro para determinar la afinidad de unión a los receptores de insulina A y B.
En estudios in vivo se evaluaron los efectos de reducción de la glucosa tras la administración subcutánea e intraperitoneal.
Se evaluó la estabilidad en la formación de suero y fibrillas en condiciones de estrés (concentración y temperatura altas).

Principales resultados:

La nueva estrategia química dio lugar a una disialo-glucosulina de alta eficiencia (aproximadamente el 60%).
La disialo-glicosulina demostró una afinidad de unión casi nativa a los receptores de insulina y potentes efectos de reducción de la glucosa in vivo.
La insulina modificada mantuvo su estructura helicoidal, mostró una mayor estabilidad en el suero humano y, lo que es crucial, no formó fibrillas.
La eficacia fue constante independientemente de la vía de administración (subcutánea versus intraperitoneal).

Conclusiones:

El método de glicosilación química desarrollado proporciona un análogo homogéneo y estable de la insulina.
La disialo-glicosulina presenta propiedades terapéuticas prometedoras, incluida una mejor estabilidad y resistencia a la formación de fibrillas.
Esta glucosulina no fibriladora es un fuerte candidato para mejorar el tratamiento de la diabetes, especialmente para su uso en bombas de insulina.

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