哈佛医学院Jonathan Abraham课题组的一项最新研究开发出HSV-1解旋酶引物酶抑制和复制叉复合物组装的机制。该研究于2025年12月29日发表于国际一流学术期刊《细胞》杂志上。
研究人员报道了与HPIs结合的单纯疱疹病毒1 H/P复合物的冷冻电镜结构，显示这些将H/P复合物锁定在非活性状态。单分子实验表明，HPIs的小鼠H/P复合物在DNA上具有解绕活性。HPIs结合的复制叉复合体的结构，包括H/P复合体（UL5， UL52和UL8）和聚合酶全酶（UL30和UL42），揭示了一个以前未被表征的连接这些复合体的界面。这些发现为理解疱疹病毒复制体组装和推进抑制剂开发提供了一个结构框架。
据介绍，疱疹病毒主题是广泛存在的双链DNA病毒主题，可建立终身潜伏期和多种疾病。尽管靶向DNA聚合酶的抗病毒药物是有效的，但不断增加的耐药性强调了寻找替代药物的必要性。解旋酶引物酶抑制剂（HPIs）是一种很有前途的抗病毒药物，但其作用机制尚不明确。此外，对于疱疹病毒主题，解旋酶-引物酶（H/P）复合体和DNA聚合酶如何协调基因组复制尚不清楚。
附：英文原文
Title: Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly
Author: Zishuo Yu, Pradeep Sathyanarayana, Cong Liu, Joel M.J. Tan, Pan Yang, Biswajit Das, Side Hu, Xiaoyi Fan, Chenggong Ji, Sandra K. Weller, Mrinal Shekhar, Donald M. Coen, Philip J. Kranzusch, Joseph J. Loparo, Jonathan Abraham
Issue&Volume: 2025-12-29
Abstract: Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.
DOI: 10.1016/j.cell.2025.11.041
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01376-5