State Key Laboratory of Veterinary Etiological Biology, OIE/National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, Gansu, China.
State Key Laboratory of Veterinary Etiological Biology, OIE/National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, Gansu, China.
Biomed Pharmacother. 2019 Oct;118:109305. doi: 10.1016/j.biopha.2019.109305. Epub 2019 Aug 10.
Foot-and-mouth disease virus (FMDV) is an important pathogen that affects livestock breeding and causes huge economic losses worldwide. Currently, the development of antiviral agents to combat FMDV infection at the early stages is being explored. As viral replication critically depends on the host for nucleoside supply, host enzymes involved in nucleotides biosynthesis may represent potential targets for the development of antiviral agents. In the present study, the effects of IMP dehydrogenase (AVN-944 and mycophenolate mofetil) and dihydroorotate dehydrogenase (teriflunomide) inhibitors were evaluated both in vitro and in vivo. The results revealed that these compounds were effective in suppressing FMDV (O/MY98/BY/2010 and A/GD/MM/2013) infection. With regard to the antiviral mechanism, time-of-addition experiments revealed that these compounds were effective when added at the early stages of viral lifecycle (0-8 h post infection). However, exogenous guanosine/uridine eliminated the antiviral activity of these compounds. Importantly, treatment AVN-944 and teriflunomide significantly improved the survival of mice that were subcutaneously treated with FMDV. Together, the results of the present study indicate the broad-spectrum activities of anti-FMDV agents targeting IMP dehydrogenase or dihydroorotate dehydrogenase, which could be useful in developing strategies to prevent FMD.
口蹄疫病毒（FMDV）是一种重要的病原体，它影响着畜牧业的发展，并在全球范围内造成了巨大的经济损失。目前，人们正在探索开发抗病毒药物，以在感染早期对抗 FMDV。由于病毒复制严重依赖宿主提供核苷，因此参与核苷酸生物合成的宿主酶可能是开发抗病毒药物的潜在靶点。在本研究中，评估了 IMP 脱氢酶（AVN-944 和霉酚酸酯）和二氢乳清酸脱氢酶（特立氟胺）抑制剂的体内外效果。结果表明，这些化合物能有效抑制 FMDV（O/MY98/BY/2010 和 A/GD/MM/2013）感染。关于抗病毒机制，添加时间实验表明，这些化合物在病毒生命周期的早期（感染后 0-8 小时）添加时有效。然而，外源性鸟苷/尿苷消除了这些化合物的抗病毒活性。重要的是，AVN-944 和特立氟胺的治疗显著提高了皮下接受 FMDV 处理的小鼠的存活率。总之，本研究结果表明，针对 IMP 脱氢酶或二氢乳清酸脱氢酶的广谱抗 FMDV 药物具有潜在的应用价值，可用于开发预防口蹄疫的策略。
