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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

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Aumentar la potencia y la amplitud de un anticuerpo contra el VIH mediante el uso de diseño racional basado en la

Ron Diskin¹, Johannes F Scheid, Paola M Marcovecchio

¹Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

Science (New York, N.Y.)

|October 29, 2011

Resumen

Se diseñaron potentes anticuerpos contra el VIH-1 dirigidos al sitio de unión CD4. Las ideas estructurales revelaron modificaciones que mejoran la amplitud y la potencia de neutralización, guiando el diseño futuro de inmunógenos para vacunas efectivas contra el VIH-1.

Área de la Ciencia:

Inmunología Inmunología.
Biología Estructural Biología estructural.
Virología Virología.

Sus antecedentes:

Los anticuerpos dirigidos al sitio de unión CD4 (CD4bs) del VIH-1 gp120 son cruciales para una neutralización potente y amplia.
VRC01 es un anticuerpo conocido dirigido a CD4bs, pero se necesita una optimización adicional para aplicaciones clínicas.

Objetivo del estudio:

Para aclarar la base estructural para la neutralización mejorada por NIH45-46, una variante de VRC01.
Para diseñar anticuerpos CD4bs mejorados a través de diseño basado en la estructura.
Para identificar los residuos clave de gp120 para la obtención de anticuerpos CD4bs.

Principales métodos:

Cristalografía de rayos X para determinar las estructuras de NIH45-46 solo y unido al VIH-1 gp120.
Diseño basado en la estructura para introducir mutaciones específicas en el anticuerpo.
Pruebas funcionales para evaluar la potencia y amplitud de neutralización de anticuerpos.

Principales resultados:

La estructura de NIH45-46 unida a gp120 reveló una inserción de cuatro residuos en CDRH3 que mejora la interacción con el dominio interno de gp120.
Una sola sustitución (G54W) en CDRH2 de NIH45-46 creó NIH45-46 (((G54W), lo que mejoró significativamente la unión a la hoja de puente gp120.
NIH45-46 ((G54W) demostró un orden de magnitud de aumento en la potencia y amplitud de neutralización en comparación con NIH45-46.

Conclusiones:

La inserción de CDRH3 en NIH45-46 contribuye a una mayor interacción con el dominio interno gp120 y una mejor neutralización.
El diseño basado en la estructura puede producir anticuerpos CD4bs muy potentes y amplios, como NIH45-46 (G54W).
La incorporación de epítopos del dominio interno gp120 y de la hoja de puente en los inmunógenos puede provocar anticuerpos CD4bs efectivos para la prevención del VIH-1.

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