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Las proteínas diseñadas ensamblan anticuerpos en nanocajas modulares
Robby Divine1,2, Ha V Dang1, George Ueda1,2
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|April 2, 2021
Resumen
El diseño computacional de las nanojaulas de anticuerpos mejora la actividad terapéutica de los anticuerpos. Estas nuevas estructuras mejoran la señalización de los receptores de la superficie celular y aumentan la neutralización de los pseudovirus SARS-CoV-2.
Área de la Ciencia:
- Biotecnología
- Biología estructural
- Inmunología
Sus antecedentes:
- La visualización multivalente de anticuerpos o ligandos puede mejorar significativamente su actividad biológica.
- Los métodos tradicionales implican la fijación de anticuerpos a andamios preexistentes, que pueden ser ineficientes.
Objetivo del estudio:
- Diseñar de forma computacional nuevas nanojaulas de anticuerpos que integren la función de anticuerpos con el ensamblaje estructural.
- Para crear pantallas de anticuerpos multivalentes utilizando nanocajas de proteínas de autoensamblaje.
Principales métodos:
- Diseño computacional de homooligómeros de unión a anticuerpos y componentes estructurales basados en anticuerpos.
- Ensamblaje de nanojaula impulsado por la interacción entre los componentes de proteínas diseñados.
- Microscopía electrónica para determinar las estructuras de las nanocajas ensambladas.
- Ensayos funcionales para evaluar las actividades de señalización y neutralización mejoradas.
Principales resultados:
- Diseñó y ensambló con éxito ocho arquitecturas de nanojaula distintas (diédrica, tetraédrica, octaédrica, icosaédrica) que muestran 2, 6, 12 y 30 anticuerpos por nanojaula.
- Las estructuras de microscopía electrónica coincidían estrechamente con los modelos computacionales.
- Se ha demostrado una mejora de la señalización mediada por receptores para el receptor de muerte 5 (DR5), el receptor de angiopoietina-1 (Tie2), la activación de CD40 y la proliferación de células T en comparación con los anticuerpos libres.
- Se mostró una mayor neutralización de los pseudovirus SARS-CoV-2 por las nanocajas de anticuerpos.
Conclusiones:
- Las nanojaulas de anticuerpos diseñadas por computación ofrecen una poderosa plataforma para crear pantallas de anticuerpos multivalentes.
- Este enfoque mejora la eficacia de los anticuerpos en varios contextos biológicos, incluida la activación inmune y la neutralización viral.
- El mecanismo de autoensamblaje proporciona una estrategia versátil para diseñar nuevas terapias basadas en proteínas.
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