Discovery of a Broad-Spectrum Antiviral Compound against Porcine Reproductive and Respiratory Syndrome Virus
Xiaopei Yang, Rumeng Ma, Yinghong Long, Wenchong Ye, Zhe Chen, Zirui Jiao, Feiming Qiu, Chuangchuang Fan, Zonghui Ma, Xiaoyang Wang, Chunmei Wang, Keyu Zhang, Wenming Chen, Zhenyu Wang, Xisong Ke, Wen ZhouAbstract
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.