Zhou Rui, Li Quanjie, Yang Bo, Quan Yanni, Liu Yitong, Liu Meichen, Zhang Yongxin, Shan Guangzhi, Li Zhourong, Wang Jing, Li Yanping, Cen Shan
CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing 100050 China.
CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantanxili, Beijing 100050 China.
Bioorg Chem. 2022 Nov;128:106024. doi: 10.1016/j.bioorg.2022.106024. Epub 2022 Jul 22.
Zika virus (ZIKV) infection can lead to severe neurological disorders and fetal defects, which has become a public health problem worldwide. However, effective clinical treatment for ZIKV infection was still arduous. Antihistamines are attractive candidates for drug repurposing due to their low price and widespread availability. Here we screened FDA-approved antihistamine drugs to obtain anti-ZIKV candidate compounds and identified mebhydrolin napadisylate (MHL) that exhibits the potent inhibition of ZIKV infection in various cell lines in a histamine H1 receptor-independent manner. Mechanistic studies suggest that MHL acts as a ZIKV NS5 RNA-dependent RNA polymerase (RdRp) inhibitor, supported by a structure-activity relationship (SAR) analysis showing the correlation between the inhibitory effect upon viral RNA synthesis and ZIKV infectivity. Furthermore, MHL was shown to bind ZIKV NS5 RdRp in vitro and predicted to interact with key residues at the active site of ZIKV NS5 RdRp by molecular docking analysis. Our data together suggest that MHL suppresses ZIKV infection through the inhibition of ZIKV NS5 RdRp activity. This study highlights that MHL might be a promising clinical anti-ZIKV therapeutic.
寨卡病毒（ZIKV）感染可导致严重的神经紊乱和胎儿缺陷，这已成为一个全球性的公共卫生问题。然而，针对ZIKV感染的有效临床治疗仍然艰巨。抗组胺药因其价格低廉且广泛可得，成为药物重新利用的有吸引力的候选药物。在此，我们筛选了美国食品药品监督管理局（FDA）批准的抗组胺药，以获得抗ZIKV候选化合物，并鉴定出萘二磺酸美海屈林（MHL），其在多种细胞系中以组胺H1受体非依赖性方式对ZIKV感染表现出强效抑制作用。机制研究表明，MHL作为ZIKV NS5 RNA依赖性RNA聚合酶（RdRp）抑制剂起作用，结构-活性关系（SAR）分析支持这一点，该分析表明对病毒RNA合成的抑制作用与ZIKV感染性之间存在相关性。此外，MHL在体外显示与ZIKV NS5 RdRp结合，并且通过分子对接分析预测其与ZIKV NS5 RdRp活性位点的关键残基相互作用。我们的数据共同表明，MHL通过抑制ZIKV NS5 RdRp活性来抑制ZIKV感染。这项研究突出表明，MHL可能是一种有前景的临床抗ZIKV治疗药物。
