Discovery of a Broad-Spectrum Antiviral Compound against Porcine Reproductive and Respiratory Syndrome Virus.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes substantial economic losses to the swine industry, while vaccine-based control remains challenges. The study performed structure-activity relationship (SAR)-guided optimization of tylvalosin, yielding 42 novel derivatives. Compound V-28 exhibited the most potent activity (PRRSV EC50 = 1.87 ± 0.25 μM; IC50 < 0.79 μM for N protein expression) with an improved selectivity index (SI = 6.62 ± 0.82). Mechanistic studies revealed that V-28 acts during viral replication, shows broad-spectrum activity, and directly binds to the STING protein (KD = 7.85 × 10-7 M), with its antiviral effect partially dependent on STING-mediated signaling. Experimental results demonstrated that V-28 exhibited an oral absolute bioavailability of 33.11% in rats, along with low genotoxicity and acute toxicity. Collectively, these findings identify V-28 as a promising tylvalosin-derived candidate compound for the development of anti-PRRSV therapeutics.