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Repurposing of antiparasitic niclosamide to inhibit respiratory syncytial virus (RSV) replication
Virus Research ( IF 2.5 ) Pub Date : 2021-01-18 , DOI: 10.1016/j.virusres.2020.198277
Nattamon Niyomdecha 1 , Ornpreya Suptawiwat 2 , Chompunuch Boonarkart 3 , Arunee Thitithanyanont 4 , Prasert Auewarakul 3
Affiliation  

Despite being an important health problem, there are only supportive care treatments for respiratory syncytial virus (RSV) infection. Thus, discovery of specific therapeutic drugs for RSV is still needed. Recently, an antiparasitic drug niclosamide has shown a broad-spectrum antiviral activity. Here, our in vitro model was used to study the antiviral effect of niclosamide on RSV and its related mechanism. Niclosamide inhibited RSV with time and dose-dependent manner. Pretreatment with submicromolar concentration of niclosamide for 6 h presented the highest anti-RSV activity of 94 % (50 % effective concentration; EC50 of 0.022 μM). Niclosamide efficiently blocked infection of laboratory strains and clinical isolates of both RSV-A and RSV-B in a bronchial epithelial cell line. Although a disruption of the mechanistic target of rapamycin complex 1 (mTORC1) pathway by niclosamide was previously hypothesized as a mechanism against pH-independent viruses like RSV, using a chemical mTORC1 inhibitor, temsirolimus, and a chemical mTORC1 agonist, MHY1485 (MHY), we show here that the mechanism of RSV inhibition by niclosamide was mTORC1 independent. Indeed, our data indicated that niclosamide hindered RSV infection via proapoptotic activity by a reduction of AKT prosurvival protein, activation of cleaved caspase-3 and PARP (poly ADP-ribose polymerase), and an early apoptosis induction.



中文翻译:

重新利用抗寄生虫药氯硝柳胺抑制呼吸道合胞病毒 (RSV) 复制

尽管是一个重要的健康问题,但对于呼吸道合胞病毒 (RSV) 感染只有支持性护理治疗。因此,仍然需要发现针对 RSV 的特异性治疗药物。最近,一种抗寄生虫药氯硝柳胺已显示出广谱抗病毒活性。在这里,我们的体外模型用于研究氯硝柳胺对 RSV 的抗病毒作用及其相关机制。氯硝柳胺以时间和剂量依赖性方式抑制RSV。用亚微摩尔浓度的氯硝柳胺预处理 6 小时表现出 94% 的最高抗 RSV 活性(50% 有效浓度;EC 500.022 μM)。Niclosamide 有效阻断了支气管上皮细胞系中 RSV-A 和 RSV-B 的实验室菌株和临床分离株的感染。尽管先前假设使用化学 mTORC1 抑制剂 temsirolimus 和化学 mTORC1 激动剂 MHY1485 (MHY),氯硝柳胺破坏雷帕霉素复合物 1 (mTORC1) 途径的机制靶标是对抗 RSV 等 pH 非依赖性病毒的机制,我们在此表明​​,氯硝柳胺抑制 RSV 的机制与 mTORC1 无关。事实上,我们的数据表明,氯硝柳胺通过减少 AKT 促存活蛋白、激活裂解的 caspase-3 和 PARP(聚 ADP-核糖聚合酶)以及早期细胞凋亡诱导来抑制 RSV 感染。

更新日期:2021-01-24
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