Los cofactores Fe-S en la ARN polimerasa dependiente del ARN del SARS-CoV-2 son objetivos antivirales potenciales

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Nunziata Maio¹, Bernard A P Lafont², Debangsu Sil³

¹Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Science (New York, N.Y.)

|June 4, 2021

Resumen

Los investigadores descubrieron grupos de hierro y azufre en la ARN polimerasa dependiente del ARN del SARS-CoV-2 (RdRp) esencial para la replicación viral. La inhibición de estos grupos con TEMPOL bloqueó la replicación del virus COVID-19, revelando un nuevo objetivo terapéutico.

Área de la Ciencia:

Virología
Biología estructural
Descubrimiento de drogas

Sus antecedentes:

El coronavirus 2 del síndrome respiratorio agudo severo (SARS-CoV-2) utiliza la ARN polimerasa dependiente del ARN (RdRp) para la replicación del genoma y la transcripción de genes.
Los modelos estructurales anteriores sugirieron centros de zinc dentro del complejo RdRp.

Objetivo del estudio:

Para investigar la naturaleza de los cofactores metálicos en la subunidad catalítica RdRp del SARS-CoV-2 (nsp12).
Explorar el potencial de estos cofactores como objetivos terapéuticos para el COVID-19.

Principales métodos:

Se utilizaron datos de microscopía cryoelectrónica para modelar los sitios de unión del metal en nsp12.
Utilizó el nitróxido estable TEMPOL para oxidar y desmontar los grupos de hierro y azufre identificados.
Se evaluó el impacto del desmontaje de los grupos en la actividad de RdRp y la replicación del SARS-CoV-2 en el cultivo celular.

Principales resultados:

Identificó dos cofactores metálicos esenciales de hierro y azufre ligados por la subunidad nsp12, distintos de los centros de zinc modelados anteriormente.
Se demostró que la oxidación y el desmontaje de estos grupos de hierro- azufre inhiben potentemente la actividad de RdRp.
Se demostró que el desmontaje del grupo inducido por TEMPOL bloqueó efectivamente la replicación del SARS-CoV-2 en el cultivo celular.

Conclusiones:

Los grupos de hierro y azufre son cofactores cruciales para la función RdRp del SARS-CoV-2 y la replicación viral.
Estos grupos de hierro y azufre representan un objetivo terapéutico prometedor para el desarrollo de nuevos tratamientos contra la COVID-19.

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