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Efectos conformacionales inducidos por la unión de protamina y zinc en análogos de insulina: un estudio experimental

Pooja Dahiya¹, Priyanka Yadav², Ankit Singh¹

¹School of Physical Sciences, Jawaharlal Nehru University, New Delhi-110067, India. mundemanoj@gmail.com.

Physical chemistry chemical physics : PCCP

|August 26, 2025

Resumen

El zinc estabiliza los análogos de la insulina lispro y el aspart. El zinc-aspart forma un hexámero más estable que el zinc-lispro, influyendo en la unión de la protamina y la dinámica de formulación para mejorar la terapia con insulina.

Área de la Ciencia:

La bioquímica
Ciencias farmacéuticas
Ciencias de los materiales

Sus antecedentes:

Los análogos de insulina son cruciales para el manejo de la diabetes, con su tiempo de acción influenciado por la formulación.
Se sabe que el zinc estabiliza la insulina promoviendo la formación de hexámero, la estructura más estable de la insulina.
Comprender la dinámica conformacional de los análogos de insulina con y sin zinc es clave para optimizar las formulaciones.

Objetivo del estudio:

Investigar la dinámica conformacional de los análogos de la insulina lispro y aspart en presencia y ausencia de zinc.
Para estudiar la interacción de estos análogos de insulina con la protamina, un componente común de la formulación.
Esclarecer la base estructural de las diferencias en la estabilidad y en la unión a la protamina entre el lispro y el aspart.

Principales métodos:

Experimentos de disociación inducida por terpiridina para evaluar la estabilidad del hexámero.
Microscopía de fuerza atómica (AFM) para analizar la heterogeneidad del ensamblaje.
Espectroscopia de dicroísmo circular (CD) para la determinación del contenido helicoidal.
Simulaciones de dinámica molecular para obtener información estructural y dinámica.
Calorimetría de titulación isotérmica (ITC) y espectroscopia de fluorescencia para estudios de unión a las protaminas.
Ensayos de unión ANS para detectar cambios de conformación.

Principales resultados:

Los análogos de insulina unidos al zinc (lispro y aspart) son más estables que sus contrapartes sin zinc.
El zinc-aspart forma una estructura hexámica más estable y consistente en comparación con el zinc-lispro, que exhibe una mayor heterogeneidad.
La protamina se une más fuertemente al hexámero de zinc-aspart estable que al zinc-lispro, con un mayor enlace de hidrógeno observado.
Ambos análogos sufren cambios conformacionales al interactuar con la protamina, exponiendo residuos hidrofóbicos.

Conclusiones:

El zinc-aspart muestra una estabilidad hexámica superior y una consistencia estructural superior al zinc-lispro.
La protamina interactúa preferentemente con el hexámero de zinc-aspart más estable, probablemente debido a su integridad estructural y polaridad.
Estos hallazgos proporcionan información crítica sobre las relaciones estructura-función de los análogos de la insulina, informando el diseño de formulaciones avanzadas de insulina.

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