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Synthesis and Mass Spectrometry Analysis of Oligo-peptoids
Published on: February 21, 2018
Síntesis en fase sólida y estudios bioquímicos de los O-boranofosfopeptidos y los O-dithiofosfopeptidos
Kenneth E Jenkins1, Adrian P Higson, Peter H Seeberger
1Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, USA.
Journal of the American Chemical Society
|June 6, 2002
Resumen
Los nuevos imitadores de fosfopéptidos, los fosfopéptidos O-borano y los fosfopéptidos O-dithio, ofrecen una mayor estabilidad e inhibición de las enzimas. Estos análogos de péptidos imitan las fosfoproteínas para el control de procesos celulares.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Química orgánica es la química orgánica.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Las vías de transducción de señales regulan las funciones celulares críticas como el crecimiento y la diferenciación a través de la fosforilación de proteínas.
- El desarrollo de análogos de péptidos estables que imiten a las fosfoproteínas es crucial para controlar estos procesos in vitro e in vivo.
Objetivo del estudio:
- Para sintetizar y caracterizar dos nuevas clases de fosfopéptidos miméticos: O-boranofosfopéptidos y O-ditiofosfopéptidos.
- Evaluar la actividad inhibidora y la estabilidad enzimática de estos nuevos miméticos contra la proteína tirosina fosfatasa (PTP) de Yersinia.
Principales métodos:
- Síntesis en fase sólida utilizando monoésteres de H-fosfonato y H-fosfonotioato con un grupo protector de 9-fluorenmetil (Fmoc) con una base lábil.
- La síntesis implicó la condensación seguida de la oxidación con complejos de borano (para los boranofosfopéptidos) o azufre elemental (para los ditiofosfopéptidos).
- Escisión del soporte sólido y desprotección utilizando hidróxido de amonio concentrado.
Principales resultados:
- Sintetizó con éxito O-boranophosphopeptides y O-dithiophosphopeptides derivados de la tirosina, la serina y la treonina.
- Los análogos de Ac-YIIPLPG-NH2 inhibieron competitivamente el Yersinia PTP, con valores de KI de 430 ± 50 μM y 670 ± 50 μM, respectivamente.
- Ambos nuevos análogos de fosfopéptidos demostraron resistencia a la hidrólisis enzimática por parte de Yersinia PTP, y los ditiofosfopéptidos fueron completamente estables durante 24 horas.
Conclusiones:
- Los O-boranofosfopéptidos y los O-ditiofosfopéptidos representan una nueva clase de imitaciones estables de la fosfoproteína.
- Estos análogos pueden servir como herramientas valiosas para estudiar y modular las vías de transducción de señales que implican la fosforilación de proteínas.
- La mayor estabilidad y propiedades inhibidoras los convierten en candidatos prometedores para aplicaciones terapéuticas o de investigación.
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