Abstract

Livestock production is vital to global food security but faces major threats from pathogens such as porcine reproductive and respiratory syndrome virus (PRRSV), which causes substantial economic losses. The genetic diversity of PRRSV and limited cross-protection among strains complicate vaccination strategies, highlighting the urgent need for effective antiviral treatments. In this study, we screened a compound library and identified 2-[(2,4-dihydroxyphenyl) sulfonyl] isoindoline-4,6-diol (designated PS10) as a potent inhibitor of PRRSV replication. PS10 exhibited dose-dependent antiviral effects in both Marc-145 cells and primary porcine alveolar macrophages, with efficacy independent of the viral strain. Further mechanistic studies revealed that PS10 acts specifically during the replication phase of the viral life cycle. Notably, PS10 significantly suppressed PRRSV infection-induced heat shock protein 90 (HSP90) expression, a critical host factor for viral replication. This suppression not only impaired viral propagation but also attenuated the production of pro-inflammatory cytokines. Furthermore, PS10 selectively reduced the abundance of multiple viral non-structural proteins (nsp2, nsp3, nsp10, and nsp11). The binding of PS10 to these proteins was confirmed by molecular docking and cellular thermal shift assays, which underlie the observed inhibition. This study not only expands our understanding of PS10’s antiviral mechanisms but also provides new insights into host factor regulation of viral replication, offering potential avenues for developing broad-spectrum antiviral therapies.