Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, China.
Vet Res. 2023 Dec 20;54(1):124. doi: 10.1186/s13567-023-01251-0.
Porcine reproductive and respiratory syndrome virus (PRRSV) infection has caused huge economic losses in global swine industry over the last 37 years. PRRSV commercial vaccines are not effective against all epidemic PRRSV strains. In this study we performed a high-throughput screening (HTS) of an FDA-approved drug library, which contained 2339 compounds, and found vidofludimus (Vi) could significantly inhibits PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages (PAMs). Compounds target prediction, molecular docking analysis, and target protein interference assay showed that Vi interacts with dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in the de novo pyrimidine synthesis pathway. Furthermore, PRRSV infection was restored in the presence of excess uridine and cytidine which promote pyrimidine salvage, or excess orotate which is the product of DHODH in the de novo pyrimidine biosynthesis pathway, thus confirming that the antiviral effect of Vi against PRRSV relies on the inhibition of DHODH. In addition, Vi also has antiviral activity against Seneca virus A (SVA), encephalomyocarditis virus (EMCV), porcine epidemic diarrhea virus (PEDV), and pseudorabies virus (PRV) in vitro. These findings should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV and other swine viral infections.
猪繁殖与呼吸综合征病毒（PRRSV）感染在过去 37 年中给全球养猪业造成了巨大的经济损失。PRRSV 商业疫苗对所有流行的 PRRSV 株都没有效果。在本研究中，我们对一个包含 2339 种化合物的美国食品和药物管理局批准的药物库进行了高通量筛选（HTS），发现 vidofludimus（Vi）可显著抑制 Marc-145 细胞和原代猪肺泡巨噬细胞（PAMs）中的 PRRSV 复制。化合物靶标预测、分子对接分析和靶蛋白干扰试验表明，Vi 与二氢乳清酸脱氢酶（DHODH）相互作用，DHODH 是从头嘧啶合成途径中的限速酶。此外，在存在促进嘧啶补救的过量尿嘧啶和胞嘧啶，或在从头嘧啶生物合成途径中 DHODH 的产物乳清酸的情况下，PRRSV 感染得以恢复，从而证实 Vi 对 PRRSV 的抗病毒作用依赖于 DHODH 的抑制。此外，Vi 还对体外的塞内卡病毒 A（SVA）、脑心肌炎病毒（EMCV）、猪流行性腹泻病毒（PEDV）和伪狂犬病病毒（PRV）具有抗病毒活性。这些发现可能有助于开发针对 PRRSV 和其他猪病毒性感染的新型预防和治疗策略。
