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Mecanismo molecular y dinámico subyacente a la resistencia a los fármacos en el genotipo 3 de la hepatitis C NS3/4A
Djadé I Soumana1, Nese Kurt Yilmaz1, Akbar Ali1
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
Journal of the American Chemical Society
|August 12, 2016
Resumen
Los inhibidores de la proteasa del virus de la hepatitis C (VHC) son menos eficaces contra el genotipo 3. Este estudio revela que las dinámicas alteradas del inhibidor de proteínas, no solo los cambios estructurales, explican esta reducida potencia, guiando el desarrollo futuro de fármacos.
Área de la Ciencia:
- Virología
- Biología estructural
- Descubrimiento de drogas
Sus antecedentes:
- El virus de la hepatitis C (VHC) afecta a 150 millones de personas en todo el mundo, causando cirrosis y cáncer de hígado.
- Los antivirales de acción directa (AAD) transformaron el tratamiento del VHC, pero la eficacia varía según el genotipo.
- Los inhibidores actuales de la proteasa NS3/4A muestran una potencia reducida contra el genotipo 3 (GT-3) del VHC.
Objetivo del estudio:
- Para aclarar la base molecular de la reducción de la potencia de los inhibidores de la proteasa NS3/4A del VHC contra el GT-3.
- Comprender los factores estructurales y dinámicos que contribuyen a la insuficiencia de PI en las infecciones GT-3.
Principales métodos:
- Diseñado una quimera GT-1a3a NS3/4A proteasa para la cristalización.
- Determinadas estructuras cristalinas de alta resolución de la quimera unidas a tres inhibidores de la proteasa.
- Se han realizado simulaciones de dinámica molecular y ensayos de inhibición.
Principales resultados:
- Se observaron diferencias estructurales sutiles entre las proteasas GT- 1 y GT- 1a3a unidas a los inhibidores.
- Se identificaron alteraciones significativas en las interacciones de enlace de hidrógeno y fluctuaciones dinámicas de los inhibidores en la quimera.
- Se encontró una fuerte correlación entre la pérdida de dinámica intermolecular y la reducción de la potencia del inhibidor.
Conclusiones:
- La potencia reducida de los inhibidores de la proteasa del VHC contra GT-3 se debe principalmente a la dinámica alterada del complejo proteico-inhibidor, no sólo a los cambios estructurales estáticos.
- Los polimorfismos genotípicos que influyen en la dinámica intermolecular son clave para comprender y superar la resistencia a la IP.
- Los hallazgos proporcionan una base molecular para diseñar terapias más efectivas contra el VHC dirigidas a diversos genotipos.
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