Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide

文献类型： 外文期刊

第一作者： Li, Yao

作者： Li, Yao;Wang, Jiongjiong;Sun, Jing;Zhang, Quan;Xu, Xiulong;Yi, Li;Cheng, Sipeng;Wang, Yongshan;Zhang, Quan;Xu, Xiulong;Zhang, Quan;Xu, Xiulong;Zhang, Quan;Xu, Xiulong

作者机构：

关键词： A77 1726; canine distemper virus; dihydroorotate dehydrogenase; janus kinase; leflunomide; p70 S6 kinase 1; pyrimidine nucleotide synthesis

期刊名称：JOURNAL OF GENERAL VIROLOGY （ 影响因子：3.376； 五年影响因子：3.035 ）

ISSN： 0022-1317

年卷期： 2021 年 102 卷 3 期

页码：

收录情况： SCI

摘要： Canine distemper virus (CDV) is the aetiological agent that causes canine distemper (CD). Currently, no antiviral drugs have been approved for CD treatment. A77 1726 is the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide. It inhibits the activity of Janus kinases (JAKs) and dihydroorotate dehydrogenase (DHO-DHase), a rate-limiting enzyme in de novo pyrimidine nucleotide synthesis. A77 1726 also inhibits the activity of p70 S6 kinase (S6K1), a serine/threonine kinase that phosphorylates and activates carbamoyl-phosphate synthetase (CAD), a second rate-limiting enzyme in the de novo pathway of pyrimidine nucleotide synthesis. Our present study focuses on the ability of A77 1726 to inhibit CDV replication and its underlying mechanisms. Here we report that A77 1726 decreased the levels of the N and M proteins of CDV and lowered the virus titres in the conditioned media of CDV-infected Vero cells. CDV replication was not inhibited by Ruxolitinib (Rux), a JAK-specific inhibitor, but by brequinar sodium (BQR), a DHO-DHase-specific inhibitor, and PF-4708671, an S6K1-specific inhibitor. Addition of exogenous uridine, which restores intracellular pyrimidine nucleotide levels, blocked the antiviral activity of A77 1726, BQR and PF-4708671. A77 1726 and PF-4708671 inhibited the activity of S6K1 in CDV-infected Vero cells, as evidenced by the decreased levels of CAD and S6 phosphorylation. S6K1 knockdown suppressed CDV replication and enhanced the antiviral activity of A77 1726. These observations collectively suggest that the antiviral activity of A77 1726 against CDV is mediated by targeting pyrimidine nucleotide synthesis via inhibiting DHO-DHase activity and S6K1-mediated CAD activation.

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