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La proteasa parecida a la papaína regula la propagación viral del SARS-CoV-2 y la inmunidad innata

Donghyuk Shin^1,2,3, Rukmini Mukherjee^1,2, Diana Grewe²

¹Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Germany.

|July 30, 2020

Resumen

El coronavirus 2 del síndrome respiratorio agudo severo (SARS-CoV-2) proteasa parecida a la papaína (PLpro) divide el ISG15, lo que dificulta la inmunidad antiviral. La inhibición del SARS-CoV-2 PLpro suprime la replicación viral y aumenta las respuestas inmunes.

Área de la Ciencia:

Virología
Biología estructural
Inmunología

Sus antecedentes:

La proteasa parecida a la papaína (PLpro) es crucial para la replicación del coronavirus y la evasión inmune del huésped.
El SARS-CoV-2 PLpro difiere del SARS-CoV PLpro en la regulación de las vías de interferón y NF-κB del huésped.

Objetivo del estudio:

Caracterizar bioquímicamente, estructuralmente y funcionalmente el SARS-CoV-2 PLpro (SCoV2-PLpro).
Para comparar SCoV2-PLpro con SARS-CoV PLpro (SCoV-PLpro) con respecto a la preferencia del sustrato huésped y la regulación de la vía inmune.
Evaluar el potencial terapéutico de la inhibición del SCoV2-PLpro.

Principales métodos:

Caracterización bioquímica y estructural de SCoV2-PLpro.
Determinación de la estructura cristalina de SCoV2-PLpro en el complejo con ISG15.
Ensayos funcionales para evaluar el ISG15 y la escisión de la cadena de ubiquitina.
Análisis del papel de SCoV2-PLpro en las respuestas al interferón y la replicación viral en las células infectadas.
Evaluación de la eficacia del inhibidor GRL-0617.

Principales resultados:

SCoV2-PLpro divide preferentemente el ISG15, a diferencia del SCoV-PLpro que se dirige a la ubiquitina.
El análisis estructural reveló interacciones de alta afinidad entre SCoV2-PLpro e ISG15.
SCoV2-PLpro separa el ISG15 del IRF3, atenuando las respuestas del interferón tipo I.
La inhibición de SCoV2-PLpro con GRL-0617 redujo la replicación viral y la citopatogenicidad al tiempo que mejoró las respuestas antivirales al interferón.

Conclusiones:

SCoV2-PLpro juega un papel importante en la patogénesis del SARS-CoV-2 al suprimir la inmunidad antiviral a través de la escisión de ISG15.
Dirigirse a SCoV2-PLpro representa una estrategia terapéutica dual prometedora para suprimir la infección por SARS-CoV-2 y reforzar la inmunidad antiviral del huésped.

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