Sanguinarine Exhibits Antiviral Activity against Porcine Reproductive and Respiratory Syndrome Virus via Multisite Inhibition Mechanisms

Porcine reproductive and respiratory syndrome virus (PRRSV), the etiological agent of PRRS, is prevalent worldwide, causing substantial and immense economic losses to the global swine industry. While current commercial vaccines fail to efficiently control PRRS, the development of safe and effective antiviral drugs against PRRSV is urgently required. Alkaloids are natural products with wide pharmacological and biological activities. Herein, sanguinarine, a benzophenanthridine alkaloid that occurs in many plants such as Macleaya cordata, was demonstrated as a potent antagonist of PRRSV. Sanguinarine attenuated PRRSV proliferation by targeting the internalization, replication, and release stages of the viral life cycle. Furthermore, ALB, AR, MAPK8, MAPK14, IGF1, GSK3B, PTGS2, and NOS2 were found as potential key targets related to the anti-PRRSV effect of sanguinarine as revealed by network pharmacology and molecular docking. Significantly, we demonstrated that the combination of sanguinarine with chelerythrine, another key bioactive alkaloid derived from Macleaya cordata, improved the antiviral activity. In summary, our findings reveal the promising potential of sanguinarine as a novel candidate for the development of anti-PRRSV agents.