Dehydrotumulosic acid: a potential glucocorticoid receptor agonist with anti-coxsackievirus activity.

BACKGROUND

Coxsackievirus infections cause a range of diseases, from hand-foot-and-mouth disease to severe conditions such as myocarditis and meningoencephalitis. High mutation rates and serotype diversity complicate clinical management, as no approved vaccines or therapies exist. Triterpenoids, natural compounds with antiviral and immunomodulatory effects, offer potential as novel treatments.

PURPOSE: This study evaluated the antiviral potential of dehydrotumulosic acid (DA), a triterpenoid derived from Poria cocos, against coxsackievirus B3 (CVB3) and other serotypes, while exploring its mechanism of action.

METHODS

The antiviral activity of DA was tested in vitro across multiple coxsackievirus serotypes using cytopathic effect inhibition, qRT-PCR(quantitative Reverse Transcription Polymerase Chain Reaction), Western blotting, and plaque assays to measure viral replication, mRNA, and protein levels. Transcriptomic profiling and cellular thermal shift assays provided mechanistic insights.

RESULTS

DA exhibited strong antiviral effects against coxsackievirus B1 (CVB1), coxsackievirus B2 (CVB2), CVB3, coxsackievirus A16 (CVA16), and coxsackievirus A (CVA6), reducing viral replication, mRNA, and protein synthesis in a dose-dependent manner without cytotoxicity. Mechanistically, DA binds and activates the glucocorticoid receptor (GR), suppressing MAPK (Mitogen-Activated Protein Kinase) /ERK(Extracellular Signal-Regulated Kinase) signaling and proinflammatory cytokine production. Compared to dexamethasone, a known GR agonist, the effects of DA were more sustained, highlighting its dual antiviral and anti-inflammatory benefits.

CONCLUSION

DA emerges as a promising host-targeted antiviral agent for coxsackievirus infections, addressing the critical unmet need for effective therapies. Its innovative dual action-combining potent antiviral activity with anti-inflammatory effects via GR activation-distinguishes it from existing approaches, offering a promising candidate for further development.