研究揭示克里米亚-刚果出血热病毒聚合酶的结构和抑制作用
研究揭示克里米亚-刚果出血热病毒聚合酶的结构和抑制作用
作者： 小柯机器人 发布时间：2026/7/23 17:20:10
本期文章：《自然》：Online/在线发表
中国科学院广州生物医药与健康研究院熊晓犁等团队近日取得一项新成果。经过不懈努力，他们提出了克里米亚-刚果出血热病毒聚合酶的结构和抑制作用。该研究于2026年7月22日发表于国际一流学术期刊《自然》杂志上。
在这里，课题组定义了体外合成CCHFV-L RNA所需的辅助因子，使捕获和测定延长的CCHFV-L-RNA复合物结构成为可能。这些结构显示出明显放大的聚合酶结构，表明CCHFV-L RNA合成伴随着聚合酶外周结构域的排序。该课题组研究人员还定义了巴洛昔韦衍生的实验药物WXSH0208和具有纳摩尔细胞效力的核苷类似物2′-脱氧-2′-氟胞苷如何分别通过内切酶抑制和易位后链终止来抑制这种聚合酶。总之，这些结果将在结构上指导针对CCHFV-L的抑制剂的合理优化。
据悉，克里米亚-刚果出血热病毒（CCHFV）是一种蜱传病毒，可导致严重的、往往致命的人类感染。由于缺乏获得许可的疫苗或药物，CCHFV是世界卫生组织优先考虑的病原体，需要紧急制定医疗对策。CCHFV Large (L)蛋白的功能是病毒RNA依赖的RNA聚合酶CCHFV-L，代表了一个有希望的抗病毒靶点，是Bunyavirales目中最大的病毒聚合酶之一。
附：英文原文
Title: Structures and inhibition of the Crimean–Congo haemorrhagic fever virus polymerase
Author: Xue, Lu, Gui, Jiacheng, Pan, Hainei, Wu, Fan, Gao, Shenghua, Kuang, Wenhua, Chang, Tiancai, Li, Zimu, Zou, Binqian, Zhao, Heyu, Li, Mei, Zhou, Min, Yuan, Hongyu, Rong, Lijun, Gong, Peng, He, Jun, Deng, Zengqin, Wang, Manli, Zhan, Peng, Chen, Xinwen, Xiong, Xiaoli
Issue&Volume: 2026-07-22
Abstract: Crimean–Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus and causes severe, often fatal, human infections. Lacking licensed vaccines or drugs, CCHFV is a World Health Organization priority pathogen requiring urgent development of medical countermeasures1,2. The CCHFV Large (L) protein functions as the viral RNA-dependent RNA polymerase CCHFV-L, representing a promising antiviral target, and is among the largest viral polymerases in the order Bunyavirales. Here we define the cofactors required for CCHFV-L RNA synthesis in vitro, enabling capture and determination of elongating CCHFV-L–RNA complex structures. The structures show a markedly enlarged polymerase architecture, revealing that CCHFV-L RNA synthesis is accompanied by ordering of the polymerase peripheral domains. We also define how the baloxavir-derived experimental drug WXSH0208 (ref. 3) and the nucleoside analogue 2′-deoxy-2′-fluorocytidine4,5, which has nanomolar cellular potency, inhibit this polymerase through endonuclease inhibition and post-translocation chain termination, respectively. Together, these results should structurally guide rational optimization of inhibitors directed against CCHFV-L.
DOI: 10.1038/s41586-026-10701-6
Source: https://www.nature.com/articles/s41586-026-10701-6
主题：结构