State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Cell Infect Microbiol. 2021 Apr 7;11:665379. doi: 10.3389/fcimb.2021.665379. eCollection 2021.
The recurring outbreak of Zika virus (ZIKV) worldwide makes an emergent demand for novel, safe and efficacious anti-ZIKV agents. ZIKV non-structural protein 5 (NS5) methyltransferase (MTase), which is essential for viral replication, is regarded as a potential drug target. In our study, a luminescence-based methyltransferase assay was used to establish the ZIKV NS5 MTase inhibitor screening model. Through screening a natural product library, we found theaflavin, a polyphenol derived from tea, could inhibit ZIKV NS5 MTase activity with a 50% inhibitory concentration (IC) of 10.10 μM. Molecular docking and site-directed mutagenesis analyses identified D146 as the key amino acid in the interaction between ZIKV NS5 MTase and theaflavin. The SPR assay indicated that theaflavin had a stronger binding activity with ZIKV NS5 wild-type (WT)-MTase than it with D146A-MTase. Moreover, theaflavin exhibited a dose dependent inhibitory effect on ZIKV replication with a 50% effective concentration (EC) of 8.19 μM. All these results indicate that theaflavin is likely to be a promising lead compound against ZIKV.
寨卡病毒（ZIKV）在全球范围内反复爆发，这就迫切需要新型、安全且有效的抗寨卡病毒药物。寨卡病毒非结构蛋白 5（NS5）甲基转移酶（MTase）是病毒复制所必需的，被认为是一个潜在的药物靶点。在本研究中，我们建立了基于发光的甲基转移酶检测法，用于寨卡病毒 NS5 MTase 抑制剂的筛选模型。通过对天然产物库进行筛选，我们发现茶黄素，一种源自茶叶的多酚类物质，能够以 50%抑制浓度（IC₅₀）为 10.10 μM 的浓度抑制寨卡病毒 NS5 MTase 活性。分子对接和定点突变分析鉴定出 D146 是寨卡病毒 NS5 MTase 与茶黄素相互作用的关键氨基酸。SPR 分析表明，茶黄素与寨卡病毒 NS5 野生型（WT）-MTase 的结合活性强于与 D146A-MTase 的结合活性。此外，茶黄素对寨卡病毒复制表现出剂量依赖性抑制作用，其 50%有效浓度（EC₅₀）为 8.19 μM。所有这些结果表明，茶黄素可能是一种有前途的抗寨卡病毒先导化合物。
