The UL23 thymidine kinase of Marek's disease virus is a target for anti-HSV drug development

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research Pub Date : 2026-03-01 Epub Date: 2026-01-14 DOI:10.1016/j.antiviral.2026.106344

Yunzhe Kang , Rui Wang , Lulu Yao , Xiuwen Yang , Wenhui Zhu , Lele Wang , Gaiping Zhang , Guoqing Zhuang , Aijun Sun

{"title":"The UL23 thymidine kinase of Marek's disease virus is a target for anti-HSV drug development","authors":"Yunzhe Kang , Rui Wang , Lulu Yao , Xiuwen Yang , Wenhui Zhu , Lele Wang , Gaiping Zhang , Guoqing Zhuang , Aijun Sun","doi":"10.1016/j.antiviral.2026.106344","DOIUrl":null,"url":null,"abstract":"<div><div>Marek's disease virus (MDV) is an oncogenic alphaherpesvirus causing rapid onset of malignant T-cell lymphomas in chickens. UL23-encoded thymidine kinase (TK) has highly conserved sequences in distinctive alphaherpesviruses. However, its enzymatic activity in viral replication and pathogenesis is poorly understood. Here, we found that the nucleotide-binding sites and the functional domains related to activity of TK from different alphaherpesviruses are strongly conserved. We show that an MDV-1 UL23-null mutation (Md5BACΔUL23) significantly reduces MDV replication in vitro and in vivo. Interestingly, chimeric viruses with replacement of MDV-1 UL23 with MDV-2, HVT, PRV, or HSV-1 UL23 showed partial recovery of MDV replication and pathogenicity. In addition, Md5BACΔUL23 infection resulted in higher survival rate and lower MDV-specific tumor incidence, which could be partially compensated by chimeric viruses. The replication properties of UL23 chimeric alphaherpesviruses are susceptible to acyclovir inhibition, whereas Md5BACΔUL23 exhibits complete resistance. Overall, our establishment of the MDV-TK chimeric model provides a robust basis for evaluating TK-targeted therapeutics, accelerating clinical translation of novel anti-herpesvirus strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"247 ","pages":"Article 106344"},"PeriodicalIF":4.0000,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antiviral research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0166354226000033","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/14 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Marek's disease virus (MDV) is an oncogenic alphaherpesvirus causing rapid onset of malignant T-cell lymphomas in chickens. UL23-encoded thymidine kinase (TK) has highly conserved sequences in distinctive alphaherpesviruses. However, its enzymatic activity in viral replication and pathogenesis is poorly understood. Here, we found that the nucleotide-binding sites and the functional domains related to activity of TK from different alphaherpesviruses are strongly conserved. We show that an MDV-1 UL23-null mutation (Md5BACΔUL23) significantly reduces MDV replication in vitro and in vivo. Interestingly, chimeric viruses with replacement of MDV-1 UL23 with MDV-2, HVT, PRV, or HSV-1 UL23 showed partial recovery of MDV replication and pathogenicity. In addition, Md5BACΔUL23 infection resulted in higher survival rate and lower MDV-specific tumor incidence, which could be partially compensated by chimeric viruses. The replication properties of UL23 chimeric alphaherpesviruses are susceptible to acyclovir inhibition, whereas Md5BACΔUL23 exhibits complete resistance. Overall, our establishment of the MDV-TK chimeric model provides a robust basis for evaluating TK-targeted therapeutics, accelerating clinical translation of novel anti-herpesvirus strategies.

查看原文本刊更多论文

马立克病病毒UL23胸苷激酶是抗hsv药物开发的靶点。

马立克病病毒（Marek's disease virus， MDV）是一种在鸡体内引起恶性t细胞淋巴瘤的致瘤性α疱疹病毒。ul23编码的胸苷激酶（TK）在不同的甲型疱疹病毒中具有高度保守的序列。然而，它在病毒复制中的酶活性和发病机制尚不清楚。本研究发现，不同甲型疱疹病毒中与TK活性相关的核苷酸结合位点和功能域都具有很强的保守性。我们发现，MDV-1 UL23-null突变（Md5BACΔUL23）在体外和体内显著减少MDV复制。有趣的是，用MDV-2、HVT、PRV或HSV-1 UL23替代MDV-1 UL23的嵌合病毒显示出MDV复制和致病性的部分恢复。此外，Md5BACΔUL23感染可导致更高的存活率和更低的mdv特异性肿瘤发生率，这可以通过嵌合病毒部分补偿。UL23嵌合α疱疹病毒的复制特性对无环鸟苷抑制敏感，而Md5BACΔUL23表现出完全的抗性。总之，我们建立的MDV-TK嵌合模型为评估tk靶向治疗提供了坚实的基础，加速了新型抗疱疹病毒策略的临床转化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Antiviral research 医学-病毒学

CiteScore

17.10

自引率

3.90%

发文量

157

审稿时长

34 days

期刊介绍： Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.