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Inhibidores picomolares de la transcriptasa inversa del VIH que presentan la sustitución bicíclica de un grupo

Won-Gil Lee¹, Ricardo Gallardo-Macias, Kathleen M Frey

¹Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.

Journal of the American Chemical Society

|October 25, 2013

Resumen

Los investigadores diseñaron nuevos compuestos bicíclicos para reemplazar un grupo reactivo en los inhibidores de la transcriptasa inversa del VIH-1. Estos nuevos inhibidores no nucleosídicos (INNRI) muestran una potente actividad contra las cepas de VIH-1 de tipo salvaje y resistentes a los medicamentos.

Área de la Ciencia:

Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Virología Virología.
Química computacional es la química computacional.

Sus antecedentes:

Los compuestos de diéter de catecol son potentes inhibidores no nucleósidos de la transcriptasa inversa del VIH-1 (INRTIs).
El actual NNRTI aprobado por la FDA rilpivirina contiene un grupo de cianovinilfenilo (CVP), lo que plantea preocupaciones de reactividad.
Se necesitan nuevos andamios químicos para desarrollar INRTIs del VIH-1 más seguros y efectivos.

Objetivo del estudio:

Diseñar y sintetizar nuevos sustitutos bicíclicos para el grupo CVP en los INNRTIs del VIH-1.
Evaluar la actividad antiviral de los compuestos diseñados contra el VIH-1 de tipo salvaje y resistente a los medicamentos.
Investigar la base estructural de la actividad y mejorar las propiedades farmacocinéticas.

Principales métodos:

Se emplearon simulaciones por computadora para diseñar nuevas estructuras de bicicletas.
Síntesis y evaluación experimental de los análogos del 2-cianoindolizinilo, el indolil y el benzofuranilo.
Los ensayos antivirales utilizan células T humanas infectadas con el tipo salvaje y el VIH-1 mutante.
Cristalografía de rayos X para determinar la estructura del complejo inhibidor-enzima.
Medición de la solubilidad en agua para los principales análogos.

Principales resultados:

Un análogo de 2-cianoindolizinyl demostró una potente actividad (EC50 = 0.4 nM) contra el VIH-1 de tipo salvaje.
Los compuestos mostraron una actividad significativa (EC50 = 10 nM) contra el VIH-1 con las mutaciones Lys103Asn/Tyr181Cys.
Los análogos de indolyl y benzofuranyl exhibieron valores de EC50 cercanos a 10 nM contra el VIH-1 de tipo salvaje.
La estructura cristalina de rayos X confirmó el modo de unión de un derivado de la 2-cianindolizina.
Los análogos de la indolizina mostraron una mejor solubilidad en agua (~ 40 μg/mL) en comparación con la rilpivirina.

Conclusiones:

Las estructuras bicíclicas de 2-cianoindolizinilo son sustitutos viables para el grupo de CVP en las ITNR del VIH-1.
Los nuevos compuestos exhiben una actividad antiviral potente y de amplio espectro, incluso contra cepas resistentes.
La mejora de la solubilidad en agua de los análogos de la indolizina sugiere el potencial de mejores perfiles farmacocinéticos.

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