In vivo antiviral activity and disassembly mechanism of novel 1-phe- nyl-5-amine-4-pyrazole thioether derivatives against Tobacco mosaic virus
In vivo antiviral activity and disassembly mechanism of novel 1-phe- nyl-5-amine-4-pyrazole thioether derivatives against Tobacco mosaic virus
复制标题
新型1-苯基-5-胺-4-吡唑硫醚衍生物对烟草花叶病毒的体内抗病毒活性及分解机制
DOI：
10.1016/j.pestbp.2021.104771
复制
发表时间：
2021-03-24
影响因子：
4.7
通讯作者：
Yang, Song
中科院分区：
文献类型：
--
作者：
Wu, Zhibing;Yang, Wenqing;Yang, Song
设计并合成了一系列新型含1，3，4-恶二唑结构的1-苯基-5-胺-4-吡唑硫醚衍生物。体内抗病毒活性测试结果表明，大部分目标化合物对烟草花叶病毒（TMV）具有较好的灭活活性。T2、T7、T9、T24、T25和T27的EC_（50）分别为15.7、15.7、15.5、11.9、12.5和16.5。g/mL，明显上级市售抗病毒药物宁南霉素（40.3？g/mL）。T24处理TMV后，AFM和TEM观察表明，T24处理后TMV的聚合长度明显缩短，并在棒状TMV上形成明显的断裂。对烟草叶片病毒侵染效率的研究表明，T24处理后病毒粒子的侵染力明显降低。T24与TMV-CP之间存在较强的相互作用（Kd = 3.8？M，得分6.11）通过MST实验观察。分子对接研究进一步表明，目标化合物与TMV CP中的氨基酸残基Glu 50相互作用，导致病毒体解体，缩短病毒体长度，降低病毒体的感染性，使目标化合物具有较高的灭活活性。该研究为通过新的作用机制和新的结合位点发现抗病毒化合物提供了新的思路。
A series of novel 1-phenyl-5-amine-4-pyrazole thioether derivatives containing a 1,3,4-oxadiazole moiety was designed and synthesised. In vivo antiviral bioassay results showed that most of the target compounds exhibited excellent inactivation activity against Tobacco mosaic virus (TMV). The EC50 values of the inactivation activities for T2, T7, T9, T24, T25 and T27 were 15.7, 15.7, 15.5, 11.9, 12.5 and 16.5 ?g/mL, respectively, which were remarkably superior over that of the commercialised antiviral agent ningnanmycin (40.3 ?g/mL). Morphological study using AFM and TEM of TMV treated with T24 showed that T24 could significantly shorten the polymerization length of TMV particles and formed a distinct break on the rod-shaped TMV. Investigations for virus infection efficiency on tobacco leaves demonstrated that infectivity of virion had been reduced obviously upon T24 treatment. Subsequently, a strong interaction between T24 and TMV-CP (Kd = 3.8 ?M, score 6.11) was observed through MST experiments. Molecular docking study further revealed that target compounds interact with amino acid residue Glu50 in TMV CP, causing disassembly of virion, shorting the length of the virion and reducing the infectivity of virion, and resulting in high inactivating activity of target compounds. This study provides a new insight for discovery of antiviral compounds through a new action mechanism with a new binding site.