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Bases moleculares de la evolución convergente de la utilización del receptor ACE2 entre los coronavirus HKU5

Young-Jun Park¹, Chen Liu², Jimin Lee³

¹Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

|February 8, 2025

Resumen

Los merbecovirus, como el HKU5, pueden usar el ACE2 para entrar en las células, distinto del entendimiento previo. Una sola mutación permite que HKU5 utilice el ACE2 humano, ayudando a la preparación para brotes contra virus emergentes.

Área de la Ciencia:

Virología
Biología molecular
Biología evolutiva

Sus antecedentes:

La dipeptidilpeptidasa 4 (DPP4) fue el receptor establecido para los merbecovirus.
Los hallazgos recientes indican que algunos coronavirus relacionados con el MERS transmitidos por murciélagos africanos utilizan la enzima de conversión de angiotensina 2 (ACE2).
El alcance del uso de ACE2 y el tropismo del receptor entre los merbecovirus es en gran medida inexplorado.

Objetivo del estudio:

Investigar la utilización de ACE2 por el merbecovirus HKU5.
Determinar la base molecular para el tropismo de la especie de HKU5.
Evaluar la antigeneidad de HKU5 e identificar los inhibidores potenciales.
Evaluar el potencial de utilización de ACE2 en la evolución y aparición del merbecovirus.

Principales métodos:

Ensayos de entrada en las células utilizando varias proteínas ACE2 de mamíferos.
Mutagénesis dirigida al sitio para identificar residuos de aminoácidos clave.
Análisis de los modos de unión y determinantes moleculares del tropismo del receptor.
Perfiles de antigenicidad y detección de fármacos para los inhibidores de HKU5.

Principales resultados:

HKU5 utiliza Pipistrellus abramus (P.abr) ACE2 y varios ACE2 de mamíferos que no son murciélagos.
Se observó un modo de unión distinto en comparación con otros coronavirus que usan ACE2.
Se identificó una sola mutación de aminoácido en la unión de HKU5 al receptor ACE2, lo que permite la utilización de ACE2 en humanos.
El MERS-CoV y el HKU5 exhiben antigeneidad significativamente diferente.
Se identificaron varios inhibidores de HKU5, incluidos dos en ensayos clínicos.

Conclusiones:

La evolución del merbecovirus incluye la adquisición independiente de la utilización de ACE2 en diferentes clados.
La capacidad de HKU5 para usar diversos ACE2 de mamíferos, incluido el ACE2 humano a través de una sola mutación, destaca el potencial pandémico.
Los resultados proporcionan una base para desarrollar contramedidas contra los merbecovirus emergentes.
El aprendizaje automático puede ayudar a predecir y prepararse para brotes virales.

Palabras clave:

HKU5 y HKU5 En el caso del MERS-CoV:anticuerpos los coronavirus Los virus del merbeco efecto de derrame Receptores virales

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