中国科学院武汉病毒研究所潘晓彦课题组近日取得一项新成果。经过不懈努力，他们研制了甘草黄酮C作为帽依赖性核酸内切酶抑制剂抗发热伴血小板减少综合征病毒的鉴定。相关论文发表在2025年4月1日出版的《中国药理学报》杂志上。

在本研究中，研究小组建立了一个基于FRET的高通量酶促筛选系统，从包含3467种天然化合物的化学文库中发现SFTSV CEN抑制剂。最后，三种化合物，即Licoflavone C， 3,4-二咖啡酰奎宁酸和齐墩果酸显示出卓越的抗病毒作用和最小的细胞毒性。选择Licoflavone C （EC50 = 1.85 μM）进行进一步研究。给药甘草黄酮C (20毫克/公斤,注射)，显著降低SFTSV攻击小鼠模型的组织病毒载量。研究人员证明了Licoflavone C不直接结合SFTSV CEN的活性口袋，而是破坏其活性构象，导致底物非竞争性抑制。除SFTSV外，Licoflavone C还对几种NSV cns （HRTV、GTV和LCMV）具有广谱抑制作用。

此外，15个具有典型类黄酮结构的Licoflavone C类似物被证实具有针对SFTSV CEN的抗病毒活性。综上所述，Licoflavone C是一种很有前景的SFTSV抑制剂，为黄酮类化合物靶向CEN的药物开发提供了新的思路。

据悉，发热伴血小板减少综合征病毒（SFTSV）是一种高致死率的蜱传病毒。目前还没有批准的药物或疫苗。SFTSV与负链分段病毒主题（nsv）共享共同的复制机制，利用L片段的帽依赖内切酶（CEN）结构域在基因组转录起始时执行帽抢夺过程。鉴于CEN在nsv生命周期中的关键作用，它被认为是发现SFTSV抗病毒药物的一个有希望的靶点。

附：英文原文

Title: Identification of Licoflavone C as a cap-dependent endonuclease inhibitor against severe fever with thrombocytopenia syndrome virus

Author: Gao, Xiao, He, Xiao-xue, Zhu, Xue-rui, Wu, Yan, Lu, Jia, Chen, Xin-lan, Zhao, Chen-shu, Li, Hao-yu, Zhang, Zhong-fa, Liu, Shu-wen, Xiao, Geng-fu, Pan, Xiao-yan

Issue&Volume: 2025-04-01

Abstract: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with a high fatality rate. Currently no approved drugs or vaccines are available against it. Sharing a common replication mechanism with negative-stranded, segmented viruses (NSVs), SFTSV utilizes a cap-dependent endonuclease (CEN) domain of the L segment to execute the cap-snatching process upon genome transcription initiation. Given the crucial role of CEN in the life cycle of NSVs, it is considered a promising target for discovery of antiviral agents against SFTSV. In this study, we established a high-throughput FRET-based enzymatic screening system to discover inhibitors of SFTSV CEN from a chemical library containing 3467 natural compounds. Finally, three compounds, i.e., Licoflavone C, 3,4-dicaffeoylquinic acid, and oleanolic acid displayed exceptional antiviral effects and minimal cytotoxicity. Licoflavone C (EC50=1.85μM) was selected for further investigation. Administration of Licoflavone C (20mg/kg, i.v.) significantly reduced tissue viral loads in SFTSV-challenged mouse model. We demonstrated that Licoflavone C did not directly bind to the active pocket of SFTSV CEN but disrupted its active conformation, resulting in substrate non-competitive inhibition. Licoflavone C also exhibited broad-spectrum inhibition on several NSV CENs (HRTV, GTV, and LCMV) besides SFTSV. Furthermore, 15 analogs of Licoflavone C sharing a typical flavonoid structure were verified for targeting SFTSV CEN and exhibiting antiviral activities. In conclusion, Licoflavone C is a promising inhibitor of SFTSV, offering insights into targeting CEN with flavonoids in drug discovery.

DOI: 10.1038/s41401-025-01533-7

Source: https://www.nature.com/articles/s41401-025-01533-7