Coumarin Derivative N6 as a Novel anti-hantavirus Infection Agent Targeting AKT.
Coumarin Derivative N6 as a Novel anti-hantavirus Infection Agent Targeting AKT.
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DOI：
10.3389/fphar.2021.745646
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发表时间：
2021
影响因子：
5.6
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Li Z;Wang F;Liu Y;Zhai D;Zhang X;Ying Q;Jia M;Xue X;Meng J;Li J;Wu X;Li M
汉坦病毒（Hantaviruses）是全球范围内新出现的人畜共患病毒，可引起亚洲和欧洲的肾综合征出血热（HFRS），主要由汉坦病毒（HTNV）感染引起，导致严重的发病率和死亡率。然而，对于这种疾病没有具体的治疗方法。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抗HTNV感染的生物活性的研究有限。为研究香豆素类化合物的抗病毒活性，合成了126个香豆素类化合物，并对其体外抗汉坦病毒活性进行了研究。在这些化合物中，N6以相对较高的选择性指数（10.9）抑制HTNV，并且在5、10和20 μM N6处理后HTNV的病毒滴度显著降低。此外，在HTNV感染的早期阶段给予N6可以抑制感染性HTNV在宿主细胞中的复制和产生，这种治疗效果在感染HTNV的早期阶段的新生小鼠中得到证实。分子对接结果表明，N6与其活性位点上的关键氨基酸残基形成相互作用，并揭示了导致所观察到的亲和力的几种分子相互作用，并且N6的处理可以显著抑制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可用作抗HTNV感染的潜在药剂。
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 in vitro. 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.
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影响因子：
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