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Resensibilización de las variantes de hepatitis C resistentes al daclatasvir mediante la modulación alosterica de

Jin-Hua Sun¹, Donald R O'Boyle¹, Robert A Fridell¹

¹Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.

|November 5, 2015

Resumen

El daclatasvir antiviral de acción directa contra el virus de la hepatitis C (VHC) muestra una mayor potencia cuando se combina con un análogo del inhibidor NS5A. Esta combinación supera la resistencia y mejora la eficacia en el tratamiento de la infección crónica por el VHC.

Área de la Ciencia:

Virología
Hepatología
Farmacología

Sus antecedentes:

El virus de la hepatitis C (VHC) infecta a más de 170 millones de personas en todo el mundo.
Las terapias antivirales de acción directa (DAA, por sus siglas en inglés) ofrecen potencial para la erradicación del VHC.
La proteína no estructural 5A del VHC (NS5A) es crucial para la replicación viral y un objetivo para los inhibidores potentes como el daclatasvir (DCV).

Objetivo del estudio:

Para comprender la potencia excepcional del daclatasvir (DCV).
Investigar el efecto sinérgico de la combinación de DCV con un análogo del inhibidor NS5A (Syn-395).
Explorar las implicaciones para el tratamiento combinado del VHC y la resistencia.

Principales métodos:

Evaluación in vitro de la actividad del DCV y del Syn-395 contra las variantes del HCV NS5A.
Evaluación de la eficacia del tratamiento combinado contra las variantes NS5A resistentes.
Validación in vivo utilizando un modelo de ratón quimérico infectado por el VHC.

Principales resultados:

DCV y Syn-395 mostraron individualmente una actividad limitada contra ciertas variantes de resistencia a NS5A.
La combinación de DCV y Syn-395 demostró una mejora de más de 1.000 veces en la potencia, restaurando la actividad al rango picomol (pM).
Se confirmó un efecto sinérgico in vivo, lo que sugiere una comunicación entre las moléculas de la proteína NS5A.

Conclusiones:

Una combinación de inhibidores NS5A puede superar la resistencia y mejorar significativamente la actividad anti-HCV.
La interacción sinérgica sugiere un mecanismo que involucra cambios conformacionales en NS5A.
Este enfoque ofrece mejores opciones para el tratamiento combinado del VHC y profundiza la comprensión de la función de NS5A.

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