近日，中國農(nóng)業(yè)科學(xué)院哈爾濱獸醫(yī)研究所聯(lián)合上海獸醫(yī)研究所，首次揭示天然小分子藥物Antimycin A通過破壞皰疹病毒復(fù)制過程中嘧啶小體的形成，抑制多種α-皰疹病毒的增殖。相關(guān)研究成果發(fā)表在Journal of Advanced Research。

該研究采用CRISPR/Cas9基因編輯技術(shù)構(gòu)建BHV-1-eGFP/Gluc重組病毒，并建立高通量抗病毒藥物篩選平臺，通過高通量篩選1500種天然小分子化合物，首次發(fā)現(xiàn)Antimycin A展現(xiàn)出顯著抗BHV-1活性，且對多種α-皰疹病毒均具有高效抑制作用。

研究人員通過代謝組學(xué)、分子對接、SPR和Co-IP等技術(shù)，揭示病毒復(fù)制需依賴宿主細(xì)胞的嘧啶核苷酸合成通路，并形成動(dòng)態(tài)代謝復(fù)合體“嘧啶小體”。結(jié)果顯示（1）抗霉素A是一種有望用于治療α-皰疹病毒感染的廣譜抗病毒藥物。（2）嘧啶體在α-皰疹病毒復(fù)制過程中組裝，以促進(jìn)嘧啶的從頭合成，這是病毒復(fù)制所必需的過程。（3）抗霉素A抑制DHODH-VDAC3相互作用，該相互作用對于嘧啶體的形成至關(guān)重要，從而抑制病毒復(fù)制。（4）抗霉素A可減少病毒復(fù)制，減輕組織病理學(xué)損傷，并提高體內(nèi)存活率。

Antimycin A抑制α-皰疹病毒感染的分子機(jī)制模式圖

中國農(nóng)業(yè)科學(xué)院哈爾濱獸醫(yī)研究所尹鑫研究員、上海獸醫(yī)研究所孫英杰研究員和哈爾濱獸醫(yī)研究所湯艷東副研究員為論文的共同通訊作者；哈爾濱獸醫(yī)研究所碩士研究生郭永琪、汪孟航副研究員和上海獸醫(yī)研究所唐寧博士后為論文的第一作者。該研究得到了黑龍江省自然科學(xué)基金項(xiàng)目（LH2024C058）資助。

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.