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Un bolsillo de enlace secundario remoto promueve la orientación heteromultivalente de DC-SIGN
Robert Wawrzinek1, Eike-Christian Wamhoff1,2, Jonathan Lefebre1,2
1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
Journal of the American Chemical Society
|November 8, 2021
Resumen
Los investigadores descubrieron una nueva forma de dirigirse a células dendríticas específicas (DC) utilizando liposomas especialmente diseñados. Este método mejora las respuestas inmunes mediante la explotación de un bolsillo de unión secundario en DC-SIGN, un receptor clave en DC.
Área de la Ciencia:
- Inmunología
- Glucosciencia
- Biotecnología
Sus antecedentes:
- Las células dendríticas (CD) son células presentadoras de antígenos cruciales que conectan la inmunidad innata y la inmunidad adaptativa.
- Los receptores de lectina tipo C como DC-SIGN y Langerin se expresan en subconjuntos específicos de DC y son objetivos para las terapias.
- Dirigirse a estos receptores ofrece potencial para la siguiente generación de inmunoterapias y anti-infecciosos.
Objetivo del estudio:
- Investigar los efectos cooperativos de los liposomas heteromultivalentes que presentan mannosidos con aglicones aromáticos y ligandos de glicanos naturales.
- Explorar el potencial para la activación alostérica de los receptores de lectina de tipo C (CLR).
- Mejorar la especificidad de las células dendríticas para aplicaciones terapéuticas.
Principales métodos:
- Se utilizaron liposomas heteromultivalentes que co-presentan mannosidos con aglicones aromáticos y ligandos glicanos naturales.
- Utilizó espectroscopia de RMN, acoplamiento molecular y simulaciones de dinámica molecular para investigaciones mecanicistas.
- Se ha probado la especificidad de la diana en las líneas celulares DC-SIGN+ y Langerin+.
Principales resultados:
- Se observaron efectos significativos de cooperatividad con liposomas heteromultivalentes en las células DC-SIGN+, pero no en las células Langerin+.
- Identificó un bolsillo de unión secundario para los glucomiméticos, alejado del sitio primario de unión de carbohidratos de DC-SIGN.
- Proporcionó evidencia preliminar para la activación alostérica del reconocimiento de glicano por la aglicona, contribuyendo a la orientación específica de DC-SIGN.
Conclusiones:
- La orientación heteromultivalente de DC puede aprovecharse a través de un bolsillo de unión secundario para mejorar la avidez y la especificidad.
- Los aglicones aromáticos pueden activar alostericamente el reconocimiento de glicanos de DC-SIGN, lo que permite la orientación específica de las células.
- Los hallazgos tienen implicaciones para la glucosciencia traslacional y el desarrollo de inmunoterapias dirigidas y antiinfecciosos.
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