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Perfiles de reactividad de redoxomas diversos de los nucleófilos de carbono
Vinayak Gupta1, Jing Yang2, Daniel C Liebler3
1Department of Chemistry, The Scripps Research Institute , Jupiter, Florida 33458, United States.
Journal of the American Chemical Society
|March 31, 2017
Resumen
Desarrollamos nuevos fragmentos nucleófilos basados en carbono para el descubrimiento de inhibidores covalentes dirigidos. Estos fragmentos reaccionan con los residuos de cisteína oxidados, expandiendo el descubrimiento de fármacos al "redoxoma" y ayudando a la investigación en la regulación redox.
Área de la Ciencia:
- Química medicinal
- Biología Química
- Proteomía
Sus antecedentes:
- Los inhibidores covalentes dirigidos son cruciales en el descubrimiento de fármacos, a menudo dirigidos a vías específicas relacionadas con la enfermedad.
- El descubrimiento de ligandos basados en fragmentos (FBLD) ha ampliado el alcance de las proteínas ligadas.
- El FBLD tradicional se basa en fragmentos reactivos a la cisteína, pero la oxidación de la cisteína en enfermedades como el cáncer limita este enfoque.
Objetivo del estudio:
- Desarrollar un nuevo método para el descubrimiento de ligandos covalentes dirigidos a residuos de cisteína oxidados.
- Para examinar una biblioteca de fragmentos nucleófilos basados en carbono contra el proteoma de una célula de cáncer de colon.
- Identificar nuevos ligandos covalentes e investigar su reactividad y preferencias de diana.
Principales métodos:
- Desarrollo de una nueva biblioteca de fragmentos nucleófilos basados en carbono.
- Evaluación de estos fragmentos frente a un proteoma de células de cáncer de colon mediante el descubrimiento de ligandos covalentes basados en fragmentos.
- Análisis de las interacciones covalentes ligando-proteína identificadas, incluidos los perfiles de reactividad y las preferencias de diana.
Principales resultados:
- Ligandos covalentes identificados para más de 1280 cisteínas S-sulfeniladas en proteínas farmacológicas y huérfanas.
- Reveló diversos perfiles de reactividad y preferencias de blanco entre los fragmentos nucleófilos C.
- Descubrió un nucleófilo de pirrolidinediona que se dirige selectivamente a las proteínas fosfatasas de tirosina.
Conclusiones:
- El descubrimiento de ligandos covalentes basados en fragmentos utilizando nucleófilos C proporciona una visión completa del "redoxoma" ligada.
- Este enfoque tiene implicaciones significativas para el desarrollo de inhibidores covalentes y la comprensión de la regulación redox en la enfermedad.
- Ofrece nuevas herramientas químicas para investigar el papel de las modificaciones redox en la función de las proteínas.
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