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Bases estructurales de una respuesta compartida de anticuerpos al SARS-CoV-2
Meng Yuan1, Hejun Liu1, Nicholas C Wu1
1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|July 15, 2020
Resumen
El gen de anticuerpo más común dirigido al dominio de unión del receptor de la proteína del pico del SARS-CoV-2 es IGHV3-53. Estos potentes anticuerpos utilizan residuos de la línea germinal, ofreciendo una vía prometedora para el diseño de nuevas vacunas.
Área de la Ciencia:
- Inmunología
- Biología estructural
- Virología
Sus antecedentes:
- Comprender las respuestas de anticuerpos neutralizantes al SARS-CoV-2 es crucial para desarrollar vacunas y terapias efectivas.
- El dominio de unión al receptor (RBD) de la proteína del pico es un objetivo primario para neutralizar los anticuerpos.
Objetivo del estudio:
- Investigar las bases moleculares de las respuestas de neutralización de anticuerpos contra el SARS-CoV-2.
- Para identificar los genes de anticuerpos utilizados con frecuencia dirigidos al RBD del SARS-CoV-2.
- Elucidar los mecanismos estructurales de unión de los anticuerpos IGHV3-53 a la RBD.
Principales métodos:
- Análisis de 294 anticuerpos contra el SARS-CoV-2.
- Determinación de las estructuras co-cristalinas de los anticuerpos neutralizantes con el RBD del SARS-CoV-2 a alta resolución.
- Análisis estructural de las interacciones anticuerpo-RBD, incluidas las contribuciones de residuos de la línea germinal y las características del bucle H3 de la región que determina la complementariedad.
Principales resultados:
- La región variable de cadena pesada de inmunoglobulina G 3-53 (IGHV3-53) es el gen más frecuente utilizado por los anticuerpos dirigidos al RBD del SARS-CoV-2.
- Las estructuras cocristalinas revelan que los residuos codificados por la línea germinal de los anticuerpos IGHV3-53 son clave para reconocer el sitio de unión ACE2.
- Este modo de unión favorece los bucles H3 cortos que determinan la complementariedad de la región y acomoda diversas cadenas ligeras, con una maduración de afinidad mínima observada.
- Los anticuerpos de IGHV3-53 muestran una alta potencia, lo que sugiere una eficacia intrínseca.
Conclusiones:
- El segmento del gen IGHV3-53 es una característica dominante de las potentes respuestas de anticuerpos neutralizantes al SARS-CoV-2.
- Los conocimientos estructurales sobre la unión de anticuerpos al IGHV3-53 proporcionan un plan para el diseño de antígenos que pueden provocar respuestas inmunes protectoras similares.
- Estos hallazgos tienen implicaciones significativas para acelerar el diseño de vacunas y el desarrollo de anticuerpos terapéuticos contra el SARS-CoV-2.
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