Zika virus (ZIKV) is a new pathogenic flavivirus transmitted by mosquitoes Aedes spp. ZIKV infection is accompanied by serious neurological complications and is especially dangerous for pregnant women, in which it can lead to congenital malformations of the fetus and microcephaly in neonates. Currently, there are no licensed vaccines or specific post-infectious therapies for ZIKV infection. This report is devoted to the study of glycyrrhizic acid (GL) derivatives as ZIKV inhibitors. The inhibitory assays on the cytopathic effect (CPE) and viral infectivity of ZIKV in three different human cell lines revealed that the conjugation of GL with amino acids and their esters (methyl, ethyl) is influenced by the antiviral activity of the compounds. GL conjugates with Glu(OMe)-OMe 11, Glu(OH)-OMe 12, Asp(OMe)-OMe 13, TyrOMe 14, LeuOEt 15, and PheOEt 16 with free COOH groups in the triterpene moiety were active against ZIKV. The most active compounds 13 and 14 have IC50 values of 0.23 μM and 0.09 μM against low doses (MOI = 0.05) of ZIKV strain PRVABC59, 1.20 μM and 0.74 μM against high doses (MOI = 10) of ZIKV strain Natal RGN single-round infectious particles, respectively. The lead compound was 14 with a high selectivity index (SI < 500). Compound 13 showed a higher inhibitory effect on the early stage (entry) of ZIKV replication than compound 14, and was less potent than compound 14 at the post-entry stage, consistent with the docking models. Compounds 13 and 14 also had a strong interaction with the active site pocket of NS5 MTase. Compounds 13 and 14 are recommended for expanded antiviral studies against ZIKV infection.

寨卡病毒（ZIKV）是一种由伊蚊（Aedes spp ）传播的新型致病性黄病毒。ZIKV 感染伴有严重的神经系统并发症，对孕妇尤其危险，可导致胎儿先天性畸形和新生儿小头畸形。目前，没有针对 ZIKV 感染的许可疫苗或特定的感染后疗法。本报告致力于研究甘草酸 (GL) 衍生物作为 ZIKV 抑制剂。对三种不同人类细胞系中 ZIKV 的细胞病变效应 (CPE) 和病毒感染性的抑制试验表明，GL 与氨基酸及其酯（甲基、乙基）的结合受化合物抗病毒活性的影响。GL 与 Glu(OMe)-OMe 11结合, Glu(OH)-OMe 12 , Asp(OMe)-OMe 13 , TyrOMe 14 , LeuOEt 15和 PheOEt 16在三萜部分具有游离 COOH 基团对 ZIKV 具有活性。最活跃的化合物13和14对低剂量 (MOI = 0.05) ZIKV 菌株 PRVABC59 的 IC50 值为 0.23 μM 和 0.09 μM，对高剂量 (MOI = 10) ZIKV 菌株 Natal RGN 单轮的 IC50 值为 1.20 μM 和 0.74 μM传染性颗粒，分别。先导化合物为14，具有高选择性指数 (SI < 500)。化合物13对 ZIKV 复制的早期（进入）显示出比化合物14更高的抑制作用，并且在进入后阶段不如化合物14有效，与对接模型一致。化合物13和14也与 NS5 MTase 的活性位点口袋有很强的相互作用。建议将化合物13和14用于针对 ZIKV 感染的扩大抗病毒研究。