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Una estabilidad estructural intrínseca mediada por bucles que modula la potencia del inhibidor en las proteasas

Rui Zeng¹, Shizhan Cui², Xiaoyan Xia¹

¹National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

|February 24, 2026

Resumen

Se determinó la estructura de la proteasa principal del coronavirus del síndrome de diarrea aguda porcina (SADS-CoV), revelando un mecanismo de inhibición novedoso. Este hallazgo ayuda en el desarrollo de terapias antivirales dirigidas contra el SADS-CoV, un patógeno zoonótico importante.

Área de la Ciencia:

Virología
Biología Estructural
Descubrimiento de Fármacos

Sus antecedentes:

El coronavirus del síndrome de diarrea aguda porcina (SADS-CoV) representa una amenaza zoonótica sustancial.
La falta de datos estructurales de la proteasa principal (Mpro) de SADS-CoV dificulta el desarrollo de fármacos antivirales.

Objetivo del estudio:

Elucidar las estructuras de alta resolución de la Mpro de SADS-CoV y sus complejos con inhibidores.
Comprender el mecanismo de inhibición novedoso y la base estructural de la potencia del inhibidor.

Principales métodos:

Se utilizó cristalografía de rayos X para determinar las estructuras de la Mpro de SADS-CoV y sus complejos inhibidores.
Se emplearon ensayos basados en células y organoides intestinales porcinos para evaluar la actividad antiviral.

Principales resultados:

Se obtuvieron estructuras de alta resolución de la Mpro de SADS-CoV con los inhibidores 27h y SY110, revelando una conformación única de hélice simple (residuos 40-53).
Esto difiere de la estructura de horquilla de hélice en la Mpro de SARS-CoV-2, lo que afecta la potencia del inhibidor.
El inhibidor 27h demostró una supresión eficiente de la replicación de SADS-CoV in vitro y en organoides.

Conclusiones:

La dinámica intrínseca de la Mpro influye significativamente en la potencia del inhibidor.
La ausencia de la 'residuos 51' en las Mpros de Alphacoronavirus es crucial para los cambios conformacionales observados.
Los hallazgos proporcionan una base para el diseño de inhibidores de Mpro de amplio espectro contra los coronavirus.

Palabras clave:

proteasa principal SADS-CoV SARS-CoV-2 inhibidor estructura antiviral estabilidad estructural dinámica Alphacoronavirus

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