Matrine activates high xenophagy to inhibit enterovirus replication

Enteroviruses continue to pose a significant public health threat due to the morbidity and mortality associated with a shortage of targeted drugs and the limited availability of existing vaccines. This underscores the need to explore effective antiviral agents.

This study examined the antiviral potential of matrine, an alkaloid extracted from Sophora species. Previous research indicated matrine's activity against Enterovirus A71 (EVA71), prompting an investigation of its effects on Enterovirus D68 (EVD68) and Coxsackievirus A6 (CVA6), as well as an exploration of its underlying mechanism.

The methods employed included western blotting, morphological analysis, immunofluorescence staining, quantitative real-time RT-PCR, TCID50, short interfering RNAs (siRNAs), knockout cell line and co-immunoprecipitation to analyze protein expression, cell death, protein localization, mRNA levels, virioin number, gene knockdown and knockout and protein binding, respectively.

Our data show that matrine has broad-spectrum antiviral activity by inhibiting the replication of EVA71, EVD68 and CVA6. Mechanistically, matrine activates autophagy to inhibit viral replication. Compared to other autophagy inducers like serum deprivation and rapamycin, matrine more effectively upregulates the expression of autophagy-related proteins LC3. Matrine directly decreases the level of the viral structural protein VP3. VP3 binds with P62, which is crucial for VP3 degradation and matrine's antiviral effect.

Matrine promotes viral protein VP3 degradation and inhibits EVA71 replication through activating high autophagy. This novel mechanism positions matrine as a promising candidate for the development of a broad-spectrum anti-enterovirus therapeutic.