Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Department of Medical Technology, Faculty of Allied Health Sciences, Thammasat University, Rangsit Campus, Pathumthani, Thailand.
Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.
Virus Res. 2021 Apr 2;295:198277. doi: 10.1016/j.virusres.2020.198277. Epub 2021 Jan 18.
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; EC 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.
尽管呼吸道合胞病毒（RSV）感染是一个重要的健康问题，但目前仅存在支持性护理治疗方法。因此，仍需要发现针对 RSV 的特定治疗药物。最近，一种抗寄生虫药物尼氯硝唑显示出广谱抗病毒活性。在这里，我们使用体外模型研究了尼氯硝唑对 RSV 的抗病毒作用及其相关机制。尼氯硝唑以时间和剂量依赖的方式抑制 RSV。亚微摩尔浓度的尼氯硝唑预处理 6 小时，对 RSV 的抗病毒活性最高，达到 94%（50%有效浓度；EC 为 0.022 μM）。尼氯硝唑能够有效阻断呼吸道合胞病毒-A 和 -B 实验室株和临床分离株在支气管上皮细胞系中的感染。尽管先前假设尼氯硝唑通过破坏雷帕霉素靶蛋白复合物 1（mTORC1）途径作为针对 pH 非依赖性病毒（如 RSV）的机制，但使用化学 mTORC1 抑制剂替西罗莫司（temsirolimus）和化学 mTORC1 激动剂 MHY1485（MHY），我们在此表明尼氯硝唑抑制 RSV 的机制与 mTORC1 无关。事实上，我们的数据表明，尼氯硝唑通过降低 AKT 生存蛋白、激活裂解的 caspase-3 和 PARP（多聚 ADP-核糖聚合酶）以及早期诱导细胞凋亡，通过促凋亡活性来抑制 RSV 感染。
