Betulonic Acid Inhibits Type-2 Porcine Reproductive and Respiratory Syndrome Virus Replication by Downregulating Cellular ATP Production

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV) infection, has been a serious threat to the pork industry worldwide and continues to bring significant economic loss. Current vaccination strategies offer limited protection against PRRSV transmission, highlighting the urgent need for novel antiviral approaches. In the present study, we reported for the first time that betulonic acid (BA), a widely available pentacyclic triterpenoids throughout the plant kingdom, exhibited potent inhibition on PRRSV infections in both Marc-145 cells and primary porcine alveolar macrophages (PAMs), with IC₅₀ values ranging from 3.3 µM to 3.7 µM against three different type-2 PRRSV strains. Mechanistically, we showed that PRRSV replication relies on energy supply from cellular ATP production, and BA inhibits PRRSV infection by reducing cellular ATP production. Our findings indicate that controlling host ATP production could be a potential strategy to combat PRRSV infections, and that BA might be a promising therapeutic agent against PRRSV epidemics.