哈兽研/上海兽研所合作发现新型广谱抗α-疱疹病毒药物

近日，中国农业科学院哈尔滨兽医研究所联合上海兽医研究所，首次揭示天然小分子药物Antimycin A通过破坏疱疹病毒复制过程中嘧啶小体的形成，抑制多种α-疱疹病毒的增殖。相关研究成果发表在Journal of Advanced Research。

该研究采用CRISPR/Cas9基因编辑技术构建BHV-1-eGFP/Gluc重组病毒，并建立高通量抗病毒药物筛选平台，通过高通量筛选1500种天然小分子化合物，首次发现Antimycin A展现出显著抗BHV-1活性，且对多种α-疱疹病毒均具有高效抑制作用。

研究人员通过代谢组学、分子对接、SPR和Co-IP等技术，揭示病毒复制需依赖宿主细胞的嘧啶核苷酸合成通路，并形成动态代谢复合体“嘧啶小体”。结果显示（1）抗霉素A是一种有望用于治疗α-疱疹病毒感染的广谱抗病毒药物。（2）嘧啶体在α-疱疹病毒复制过程中组装，以促进嘧啶的从头合成，这是病毒复制所必需的过程。（3）抗霉素A抑制DHODH-VDAC3相互作用，该相互作用对于嘧啶体的形成至关重要，从而抑制病毒复制。（4）抗霉素A可减少病毒复制，减轻组织病理学损伤，并提高体内存活率。

Antimycin A抑制α-疱疹病毒感染的分子机制模式图

中国农业科学院哈尔滨兽医研究所尹鑫研究员、上海兽医研究所孙英杰研究员和哈尔滨兽医研究所汤艳东副研究员为论文的共同通讯作者；哈尔滨兽医研究所硕士研究生郭永琪、汪孟航副研究员和上海兽医研究所唐宁博士后为论文的第一作者。该研究得到了黑龙江省自然科学基金项目（LH2024C058）资助。

附文章信息：

Title：Antimycin A inhibits alpha-herpesvirus replication by disrupting the formation of pyrimidinosomes

Highlights：（1）Antimycin A emerges as a promising broad-spectrum antiviral agent against alpha-herpesvirus infections.（2）Pyrimidinosomes assemble during alpha-herpesvirus replication to facilitate de novo pyrimidine synthesis, a process essential for viral replication.（3）Antimycin A inhibits the DHODH-VDAC3 interaction, which is essential for pyrimidinosome formation, thereby impairing viral replication.（4）Antimycin A reduces viral replication, mitigates histopathological damage, and enhances survival rates in vivo.

Abstract：Introduction，Alpha-herpesvirus poses significant health risks to humans and challenges to animal husbandry. Currently, the clinically approved antiviral drug Acyclovir exhibits limitations, including drug resistance and adverse effects. The development of broad-spectrum antiviral agents against alpha-herpesvirus is urgently needed.Objective，This study aimed to discover a novel antiviral drug with the capacity to broadly inhibit various alpha-herpesviruses.Methods，In this study, we conducted a high-content screening of 1,500 chemical compounds to identify potential antiviral candidates. The antiviral mechanisms were explored using phenotypic experiments, untargeted metabolomics, and molecular docking.Results，We discovered that Antimycin A effectively inhibits the replication of various alpha-herpesviruses, including herpes simplex virus 1 (HSV-1), bovine herpesvirus 1 (BHV-1), and pseudorabies virus (PRV). Our study revealed that Antimycin A inhibits viral replication by disrupting the formation of pyrimidinosomes that are essential for efficient viral infection. Finally, Antimycin A effectively inhibited viral infection, prevented tissue damage, and enhanced survival in PRV-infected BALB/c mice, confirming its in vivo efficacy.Conclusion，Antimycin A emerges as a promising lead candidate for the development of antiviral therapies against alpha-herpesvirus infections.

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