Small-molecule PS10 inhibits PRRSV replication by targeting HSP90 and multiple viral non-structural proteins

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• Porcine reproductive and respiratory syndrome virus (PRRSV) poses a significant threat to global swine production and food security.
• Existing vaccines for PRRSV often exhibit limited cross-protection against diverse viral strains, necessitating the development of alternative treatments.
• The genetic variability of PRRSV complicates effective disease management strategies.

Purpose of the Study:

• To identify novel antiviral compounds targeting PRRSV replication.
• To elucidate the mechanism of action of identified inhibitors.
• To evaluate the potential of new therapeutic agents for controlling PRRSV infections.

Main Methods:

• Compound library screening to identify PRRSV inhibitors.
• Antiviral assays in cell cultures (Marc-145 cells) and primary porcine alveolar macrophages.
• Mechanistic studies including heat shock protein 90 (HSP90) expression analysis, cytokine profiling, viral non-structural protein quantification, molecular docking, and cellular thermal shift assays (CETSA).

Main Results:

• 2-[(2,4-dihydroxyphenyl) sulfonyl] isoindoline-4,6-diol (PS10) was identified as a potent inhibitor of PRRSV replication.
• PS10 demonstrated dose-dependent antiviral activity across different PRRSV strains and host cells, with low cytotoxicity.
• PS10 suppressed PRRSV-induced HSP90 expression, reduced pro-inflammatory cytokine production, and decreased levels of viral non-structural proteins (nsp2, nsp3, nsp10, nsp11) through direct binding.

Conclusions:

• PS10 is a promising antiviral agent effective against PRRSV by targeting critical viral and host factors.
• The study provides insights into PS10's mechanism, including its interaction with viral proteins and modulation of host responses.
• PS10 offers a potential foundation for developing novel, broad-spectrum antiviral therapies for PRRSV and potentially other viral infections.