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Un principio químico general para crear inhibidores de integrina estabilizadores de cierre
Fu-Yang Lin1, Jing Li1, Yonghua Xie2
1Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell
|September 16, 2022
Resumen
Los inhibidores de la integrina de molécula pequeña pueden fallar al estabilizar las conformaciones activas. Una característica química recientemente identificada, un átomo de nitrógeno polar, puede estabilizar las conformaciones de integrinas inactivas, ofreciendo una nueva estrategia de diseño de fármacos.
Área de la Ciencia:
- La bioquímica
- Farmacología
- Biología estructural
Sus antecedentes:
- Las integrinas son objetivos farmacológicos cruciales, con terapias aprobadas disponibles.
- Los inhibidores de moléculas pequeñas anteriores para las integrinas (αIIbβ3, α4β1) fallaron en ensayos en etapa tardía para enfermedades crónicas.
- El agonismo parcial, que estabiliza los estados de integración de alta afinidad, es una causa potencial de estas fallas.
Objetivo del estudio:
- Investigar por qué ciertos inhibidores de la integrina de pequeñas moléculas fallaron en ensayos clínicos.
- Identificar los mecanismos estructurales subyacentes a la inhibición de la integrina.
- Descubrir nuevos principios de diseño de fármacos para desarrollar antagonistas eficaces de la integrina.
Principales métodos:
- Ensayos bioquímicos para evaluar la conformación de las integrinas.
- Análisis estructural de los inhibidores de moléculas pequeñas unidos a las integrinas.
- Estudios de la relación estructura-actividad para identificar las características químicas clave.
Principales resultados:
- Se encontró que los inhibidores de moléculas pequeñas de las integrinas αIIbβ3 y α4β1 no estabilizaban la conformación de alta afinidad extendida.
- Se identificó una nueva característica química (átomo de nitrógeno polar) en los antagonistas de αIIbβ3 que estabiliza la conformación de baja afinidad y cerrada.
- Esta estabilización implica una molécula de agua en el sitio de adhesión dependiente de iones metálicos (MIDAS), evitando la transición al estado abierto.
Conclusiones:
- El agonismo parcial mediante la estabilización de las conformaciones activas contribuye al fracaso de algunos inhibidores de la integrina.
- Se puede explotar una característica química simple, un nitrógeno polar, para diseñar inhibidores que estabilicen la conformación inactiva de la integrina.
- Este principio de diseño de fármacos muestra una amplia aplicabilidad en toda la familia de integrinas, como se demuestra con la integrina α4β1.
Palabras clave:
agonismoEnfermedad autoinmuneEspecificidad de conformaciónCambio de conformaciónConformacionesdescubrimiento de fármacosEnlaces de hidrógenoInhibidores de la integrinaLas integrinasReceptores de membranaTrombosisClasificación de las sustanciasEn el caso de las sustancias activas, se utilizará la fórmula:Más Videos Relacionados
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