Replication of peste des petits ruminants virus (PPRV) strongly depends on the cellular environment and resources of host cells including nucleoside pool. Thus, enzymes involved in nucleoside biosynthesis (such as pyrimidine biosynthesis pathway) are regarded as attractive targets for antiviral drug development. Here, we demonstrate that brequinar (BQR) and leflunomide (LFM) which are two specific inhibitors of DHODH enzyme and 6-azauracil (6-AU) which is an ODase enzyme inhibitor robustly inhibit PPRV replication in HEK293T cell line as well as in peripheral blood mononuclear cells isolated from goat. We further demonstrate that these agents exert anti-PPRV activity via the depletion of purimidine nucleotide. Interestingly, these inhibitors can trigger the transcription of antiviral interferon-stimulated genes (ISGs). However, the induction of ISGs is largely independent of the classical JAK-STAT pathway. Combination of BQR with interferons (IFNs) exerts enhanced ISG induction and anti-PPRV activity. Taken together, this study reveals an unconventional novel mechanism of crosstalk between nucleotide biosynthesis pathways and cellular antiviral immunity in inhibiting PPRV replication. In conclusion, targeting pyrimidine biosynthesis represents a potential strategy for developing antiviral strategies against PPRV.

小反刍兽疫病毒 (PPRV) 的复制在很大程度上取决于宿主细胞的细胞环境和资源，包括核苷池。因此，参与核苷生物合成（如嘧啶生物合成途径）的酶被认为是抗病毒药物开发的有吸引力的靶点。在这里，我们证明了作为 DHODH 酶的两种特异性抑制剂的布雷奎那 (BQR) 和来氟米特 (LFM) 和作为 ODase 酶抑制剂的 6-氮杂尿嘧啶 (6-AU) 在 HEK293T 细胞系和外周细胞中强烈抑制 PPRV 复制。从山羊中分离出的血液单核细胞。我们进一步证明这些药剂通过消耗嘌呤核苷酸发挥抗 PPRV 活性。有趣的是，这些抑制剂可以触发抗病毒干扰素刺激基因 (ISG) 的转录。然而，ISGs 的诱导很大程度上独立于经典的 JAK-STAT 通路。BQR 与干扰素 (IFN) 的组合可增强 ISG 诱导和抗 PPRV 活性。总之，这项研究揭示了核苷酸生物合成途径和细胞抗病毒免疫之间在抑制 PPRV 复制方面的一种非常规新机制。总之，靶向嘧啶生物合成代表了开发针对 PPRV 的抗病毒策略的潜在策略。