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Bases estructurales de la acción del inhibidor de la integrasa del VIH de segunda generación y la resistencia viral
Nicola J Cook1, Wen Li2,3, Dénes Berta4
1Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London NW1 1AT, UK.
Science (New York, N.Y.)
|February 1, 2020
Resumen
Los inhibidores de transferencia de cadenas de la integrasa del VIH de segunda generación (INSTIs) como el dolutegravir son efectivos debido a sus estructuras químicas avanzadas. Estas estructuras superan las mutaciones de resistencia INSTI mediante la mejora de las interacciones dentro del sitio activo de la enzima integrasa del VIH.
Área de la Ciencia:
- Biología estructural
- Virología
- Química medicinal
Sus antecedentes:
- Los inhibidores de transferencia de cadena de la integrasa del VIH (INSTIs) de segunda generación se utilizan ampliamente para el tratamiento del VIH.
- Los mecanismos precisos que subyacen a su mayor eficacia, particularmente contra las cepas resistentes, siguen siendo incompletamente entendidos.
Objetivo del estudio:
- Elucidar los mecanismos moleculares de los INSTIs avanzados, específicamente el dolutegravir y el bictegravir, con una resolución casi atómica.
- Para entender cómo estos medicamentos superan las mutaciones comunes de resistencia INSTI.
Principales métodos:
- Para visualizar las interacciones fármaco-objetivo se empleó la criomicroscopia electrónica de partícula única (Cryo-EM).
- El análisis estructural se centró en el sitio activo de la enzima integrasa del VIH y su interacción con los INSTIs.
Principales resultados:
- Las estructuras cryo-EM de resolución casi atómica revelaron cómo dolutegravir y bictegravir se unen a la integrasa del VIH.
- Se demostró que las mutaciones clave de resistencia (Q148H y G140S) interrumpen la coordinación de iones de magnesio, una debilidad crítica.
- Los andamios químicos expandidos de los INSTIs de segunda generación permiten interacciones cruciales con la columna vertebral de proteínas, antagonizando las variantes virales resistentes.
Conclusiones:
- El estudio proporciona una base estructural para la actividad superior de los INSTIs de segunda generación contra las cepas de VIH con mutaciones de resistencia comunes.
- Comprender el papel de la unión de iones de magnesio en la función farmacófora de INSTI ofrece un marco para el desarrollo de terapias anti-VIH/SIDA de próxima generación.
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