近日，中国科学院武汉病毒研究所龚鹏及其小组提出了CCHFV聚合酶的RNA合成机制及抑制剂研究。这一研究成果发表在2026年7月22日出版的国际学术期刊《自然》上。

在这里，课题组报告了全长奈罗病毒科克里米亚-刚果出血热病毒（CCHFV） L的结构，包括3.0--分辨率聚合酶延伸复合物，阐明了早期和晚期延伸阶段的机制。在CCHFV L的三个主要功能区域都发现了大量的添加和插入，这些区域包含内切酶、RNA依赖性RNA聚合酶（RdRP）和帽结合域，扩展了RdRP活性位点两侧的RNA结合路径，并创建了对病毒复制至关重要的相互作用网络，这是CCHFV微小基因组分析数据所表明的。与丙型肝炎药物索非布韦相同的具有核糖2 -修饰的NAs通过立即链终止机制特异性有效地抑制CCHFV RdRP。以索非布韦-丙型肝炎病毒RdRP系统为参照，在存在相应NTP的竞争试验中进一步证明了这些NAs的效力。

据介绍，来自奈洛病毒科的约4000个残基L蛋白是已知最大的病毒聚合酶，缺乏全局结构信息和有前途的核苷酸类似物（NA）抑制剂。

附：英文原文

Title: RNA synthesis and substrate analog inhibition in the CCHFV polymerase

Author: Jia, Hengxia, Tang, Bo, Liu, Shunli, Wen, Xin, Wu, Fan, Hu, Xiao, Zhou, Hu, Chong, Tingting, Lv, Lincan, Liu, Qiaojie, Rao, Guibo, Wei, Mingyu, Jing, Xuping, Cao, Sheng, Deng, Fei, Hu, Zhihong, Shu, Bo, Gong, Rui, Wu, Jiqin, Wang, Manli, Gong, Peng

Issue&Volume: 2026-07-22

Abstract: The about 4000-residue L proteins from the Nairoviridae are the largest known viral polymerases, lacking global structural information and promising nucleotide analog (NA) inhibitors. Here we report structures of full-length Nairoviridae Crimean-Congo hemorrhagic fever virus (CCHFV) L including a 3.0--resolution polymerase elongation complex that elucidates mechanisms of both early and late elongation stages. Large additions and insertions are found in all three major functional regions that contain the endonuclease, RNA-dependent RNA polymerase (RdRP), and cap-binding domain of CCHFV L, extending RNA binding paths on both sides of RdRP active site and creating interaction networks critical for virus replication as suggested by CCHFV minigenome assay data. NAs with ribose-2′-modifications identical to the hepatitis C drug sofosbuvir are found to specifically and efficiently inhibit CCHFV RdRP through immediate chain termination mechanism. Using sofosbuvir-hepatitis C virus RdRP system as the reference, the potency of these NAs is further demonstrated in competition assays in the presence of corresponding NTPs.

DOI: 10.1038/s41586-026-10913-w

Source: https://www.nature.com/articles/s41586-026-10913-w

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html