Repurposing of the antihistamine mebhydrolin napadisylate for treatment of Zika virus infection

被引：8

作者：

Zhou, Rui ^{[1
]}

Li, Quanjie ^{[1
]}

Yang, Bo ^{[1
]}

Quan, Yanni ^{[1
]}

Liu, Yitong ^{[1
]}

Liu, Meichen ^{[1
]}

Zhang, Yongxin ^{[1
]}

Shan, Guangzhi ^{[1
]}

Li, Zhourong ^{[1
]}

Wang, Jing ^{[1
]}

Li, Yanping ^{[1
]}

Cen, Shan ^{[1
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, CAMS Key Lab Antiviral Drug Res, 1 Tiantanxili, Beijing 100050, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2022年 / 128卷

基金：

中国国家自然科学基金;

关键词：

Zika Virus; Antihistamine drugs; Anti-virus; RNA-dependent RNA polymerase; Antiviral agents; CRYSTAL-STRUCTURE; RNA-SYNTHESIS; IDENTIFICATION; INHIBITORS; DOMAIN; SCREEN;

D O I：

10.1016/j.bioorg.2022.106024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：10