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Ingeniería de la plasticidad conformacional de SIRPα para revelar un bolsillo críptico adecuado para el diseño de

M Storder¹, S Barelier¹, F Cordier^2,3

¹CRCM, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille Univ, Marseille, France.

bioRxiv : the preprint server for biology

|January 7, 2026

Resumen

Los investigadores descubrieron un nuevo bolsillo tratable en SIRPα, un objetivo clave para la inmunoterapia contra el cáncer. Este bolsillo críptico

Área de la Ciencia:

Bioquímica
Biología Estructural
Inmunología

Sus antecedentes:

La interacción entre la proteína alfa reguladora de la señal (SIRPα) y CD47 es un punto de control inmunitario crucial explotado por los tumores para la evasión inmunitaria.
Las terapias con anticuerpos existentes dirigidas a este punto de control enfrentan desafíos debido a la interfaz de unión plana, lo que limita el desarrollo de inhibidores de moléculas pequeñas.

Objetivo del estudio:

Identificar nuevos sitios tratables dentro de SIRPα para el desarrollo de inhibidores de moléculas pequeñas.
Caracterizar el mecanismo que controla el acceso a un bolsillo críptico recién descubierto en SIRPα.

Principales métodos:

Cribado de fragmentos basado en la estructura utilizando cristalografía de rayos X.
Espectroscopía de RMN, simulaciones de dinámica molecular y ensayos biofísicos.
Mutagénesis dirigida para diseñar variantes de SIRPα.

Principales resultados:

Descubrimiento de un bolsillo críptico novedoso y tratable (bolsillo WYF) en el dominio D1 de SIRPα.
Identificación de Gln52 como residuo guardián que controla la accesibilidad del bolsillo a través del equilibrio conformacional.
Los mutantes de SIRPα diseñados demostraron una afinidad de unión alterada a CD47 y una unión mejorada a fragmentos de moléculas pequeñas.

Conclusiones:

SIRPα posee plasticidad conformacional intrínseca que permite el objetivo de bolsillos crípticos.
Se valida una estrategia de 'flexibilidad para la inhibición', que atrapa una conformación no unida, para el desarrollo de inhibidores alostéricos.
Este enfoque proporciona una hoja de ruta para dirigirse a SIRPα-CD47 y otros puntos de control inmunitarios difíciles.

Palabras clave:

inmunoterapia contra el cáncer inhibidores alostéricos punto de control inmunitario SIRPα-CD47 diseño de fármacos bolsillo críptico plasticidad conformacional

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