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Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause significant economic loss worldwide and remains a serious threat to the pork industry. Currently, vaccination strategies provide limited protection against PRRSV infection, and consequently, new antiviral strategies are urgently required. Andrographolide (Andro) and its derivative potassium dehydrographolide succinate (PDS) have been used clinically in China and other Asian countries as therapies for inflammation-related diseases, including bacterial and viral infections, for decades. Here, we demonstrate that Andro and PDS exhibit robust activity against PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages (PAMs). The two compounds exhibited broad-spectrum inhibitory activities in vitro against clinically circulating type 2 PRRSV GD-HD, XH-GD, and NADC30-like HNhx strains in China. The EC(50) values of Andro against three tested PRRSV strain infections in Marc-145 cells ranged from 11.7 to 15.3 μmol/L, with selectivity indexes ranging from 8.3 to 10.8, while the EC(50) values of PDS ranged from 57.1 to 85.4 μmol/L, with selectivity indexes ranging from 344 to 515. Mechanistically, the anti-PRRSV activity of the two compounds is closely associated with their potent suppression on NF-κB activation and enhanced oxidative stress induced by PRRSV infection. Further mechanistic investigations revealed that PDS, but not Andro, is able to directly interact with PRRSV particles. Taken together, our findings suggest that Andro and PDS are promising PRRSV inhibitors in vitro and deserves further in vivo studies in swine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12250-021-00455-y.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Therefore, there is an urgent need to develop new antiviral strategies to prevent PRRSV pandemics. In this study, we showed that 3-O-β-chacotriosyl ursolic acid (1) and its ester analogs possessed anti-PRRSV activity in vitro, of which bioisosteric surrogates 7–15 were further generated with the aim of enhancing the selective index. Our results showed that amidation of the 17-COOH group of UA could significantly reduce cytotoxicity and enhance anti-PRRSV activity in MARC-145 cells. Among them, compound 9 displayed the strongest anti-PRRSV activity with the least cytotoxicity. Potent inhibition of representative compounds 9 and 12 on PRRSV infection was observed not only in MARC-145 cells, but also in primary porcine alveolar macrophages, PRRSV-target cells in vivo. Furthermore, compounds 8, 9, 12 and 14 exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV NADC30-like and GD-XH strains as well as classical CH-1a and VR2332 strains. Mechanistically, compounds 9 and 12 inhibited PRRSV replication by directly inactivating virions and therefore affecting all tested stages of the virus life cycle, including viral entry, replication and progeny virus release, but did not affect cellular susceptibility to PRRSV. Our findings suggest that compound 9 could be a hit PRRSV inhibitor and deserves further in vivo studies in swine.