Bases estructurales para la inhibición de la ARN polimerasa dependiente del ARN del SARS-CoV-2 por remdesivir

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Wanchao Yin^1,2, Chunyou Mao², Xiaodong Luan^3,4,5

¹The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Science (New York, N.Y.)

|May 3, 2020

Resumen

El análisis estructural de la ARN polimerasa dependiente del ARN del SARS-CoV-2 revela cómo el remdesivir inhibe la replicación viral. Las estructuras cryo-EM proporcionan una plantilla para diseñar nuevos medicamentos antivirales contra el COVID-19.

Área de la Ciencia:

Biología estructural
Virología
Descubrimiento de drogas

Sus antecedentes:

La pandemia de COVID-19, causada por el SARS-CoV-2, requiere estrategias antivirales efectivas.
La ARN polimerasa dependiente del ARN del SARS-CoV-2 (RdRp) es crucial para la replicación viral y un objetivo de fármaco clave.

Objetivo del estudio:

Para determinar las estructuras de microscopía criolectrónica de alta resolución del SARS-CoV-2 RdRp.
Aclarar el mecanismo de incorporación y terminación de la cadena de remdesivir durante la síntesis del ARN viral.

Principales métodos:

Se utilizó la criomicroscopia electrónica (Cryo-EM) para resolver la estructura del RdRp del SARS-CoV-2.
Se determinaron estructuras para la forma apo y en complejo con ARN y remdesivir.

Principales resultados:

La estructura apo RdRp se resolvió a 2,8 angstroms.
La estructura compleja, a 2,5 angstroms, muestra ARN en el canal central y remdesivir incorporado en la hebra del primer.
La incorporación de remdesivir conduce a la terminación del alargamiento de la cadena de ARN.

Conclusiones:

Las estructuras determinadas ofrecen información detallada sobre el mecanismo de replicación del ARN del SARS-CoV-2.
Estos hallazgos proporcionan una base estructural para el diseño racional de nuevas terapias antivirales dirigidas a SARS-CoV-2 RdRp.

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