Li Zhoupeng, Wang Fang, Liu Yongsheng, Zhai Dongshen, Zhang Xiaoxiao, Ying Qikang, Jia Min, Xue Xiaoyan, Meng Jingru, Li Jing, Wu Xingan, Li Mingkai
Department of Pharmacology and Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medical of the State Administration of Traditional Chinese Medicine, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
Department of Microbiology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, China.
Front Pharmacol. 2021 Dec 6;12:745646. doi: 10.3389/fphar.2021.745646. eCollection 2021.
Hantaviruses are globally emerging zoonotic viruses that can cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, which is primarily caused by Hantaan virus (HTNV) infection, results in profound morbidity and mortality. However, no specific treatment is available for this disease. Coumarin derivatives have been reported as antiviral molecules, while studies about the bioactivity of coumarin derivatives against HTNV infection are limited. To study the potential antiviral activity of coumarin derivatives, 126 coumarin derivatives are synthesized, and their inhibitory activity against HTNV is analyzed . Among these compounds, N6 inhibits HTNV with relatively high selectivity index at 10.9, and the viral titer of HTNV is reduced significantly after 5, 10, and 20 μM N6 treatments. Furthermore, the administration of N6 at the early stage of HTNV infection can inhibit the replication and production of infectious HTNV in host cell, this therapeutic efficacy is confirmed in HTNV-infected newborn mice at the early stage of infection. The molecular docking results show that N6 forms interactions with the key amino acid residues at its active site, and reveals several molecular interactions responsible for the observed affinity, and the treatment of N6 can inhibit the expression of p (Ser473)Akt and HTNV nucleocapsid protein significantly. As such, these observations demonstrate that coumarin derivative N6 might be used as a potential agent against HTNV infection.
汉坦病毒是全球范围内新出现的人畜共患病毒，在亚洲和欧洲可引起肾综合征出血热（HFRS），主要由汉滩病毒（HTNV）感染所致，会导致严重的发病和死亡。然而，这种疾病尚无特效治疗方法。香豆素衍生物已被报道为抗病毒分子，但关于香豆素衍生物对HTNV感染的生物活性研究有限。为研究香豆素衍生物的潜在抗病毒活性，合成了126种香豆素衍生物，并分析了它们对HTNV的抑制活性。在这些化合物中，N6以相对较高的选择性指数10.9抑制HTNV，在5、10和20μM N6处理后，HTNV的病毒滴度显著降低。此外，在HTNV感染早期给予N6可抑制宿主细胞中传染性HTNV的复制和产生，这种治疗效果在HTNV感染的新生小鼠感染早期得到证实。分子对接结果表明，N6与其活性位点的关键氨基酸残基形成相互作用，揭示了几种导致观察到的亲和力的分子相互作用，并且N6处理可显著抑制p（Ser473）Akt和HTNV核衣壳蛋白的表达。因此，这些观察结果表明香豆素衍生物N6可能用作抗HTNV感染的潜在药物。
