Yang Yuyuan, Zhang Jian, Li Xiangyang, He Fangcheng, Wu Rong, Hu Deyu, Song Baoan
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China.
ACS Omega. 2020 Aug 26;5(35):22596-22602. doi: 10.1021/acsomega.0c03306. eCollection 2020 Sep 8.
Tobacco mosaic virus coat protein (TMV CP) plays an important role in viral replication, translation, and intracellular and intercellular movements. Thus, TMV CP could be regarded as a potential target for antiviral agents. In this study, in order to find out whether dithioacetal derivatives act on the CP target, a series of dithioacetal derivatives containing sulfonamide moiety was first designed and synthesized. Bioassay results demonstrated that , , and exhibited excellent activities against TMV, with half-maximal effective concentrations (EC) of the curative, protective, and inactivate activities being 183.0 ± 3.2, 252.3 ± 2.6, and 63.8 ± 1.2 μg/mL, 270.6 ± 3.7, 249.7 ± 3.5, and 57.7 ± 1.4 μg/mL, and 329.5 ± 1.5, 269.2 ± 3.7, and 48.1 ± 2.0 μg/mL for , , and , respectively, which were higher than those for the control agents ningnanmycin (331.0 ± 2.8, 271.0 ± 2.8, and 77.4 ± 1.3 μg/mL, respectively) and (471.5 ± 1.4, 447.2 ± 2.1, and 91.7 ± 1.8 μg/mL, respectively). Transmission electron microscopy showed that the particle morphology of TMV was destroyed by , and microscale thermophoresis (MST) showed that bonded to CP with a dissociation constant ( ) of 9.7 ± 1.7 μM. Then, molecular docking and MST further illustrated that had a weak binding affinity with the TMV mutant protein ( = 561.3 ± 83.2 μM). Thus, we deduced that the dithioacetal derivative may inhibit TMV activity by binding TMV CP. This work provides some new insights for the design and optimization of novel anti-TMV agents.
烟草花叶病毒外壳蛋白（TMV CP）在病毒复制、翻译以及细胞内和细胞间运动中发挥着重要作用。因此，TMV CP可被视为抗病毒药物的潜在靶点。在本研究中，为了探究二硫缩醛衍生物是否作用于CP靶点，首先设计并合成了一系列含有磺酰胺部分的二硫缩醛衍生物。生物测定结果表明，[具体化合物1]、[具体化合物2]和[具体化合物3]对TMV表现出优异的活性，其治疗、保护和灭活活性的半数有效浓度（EC）分别为183.0±3.2、252.3±2.6和63.8±1.2μg/mL，[具体化合物1]为270.6±3.7、249.7±3.5和57.7±1.4μg/mL，[具体化合物3]为329.5±1.5、269.2±3.7和48.1±2.0μg/mL，均高于对照药剂宁南霉素（分别为331.0±2.8、271.0±2.8和77.4±1.3μg/mL）和[对照药剂2]（分别为471.5±1.4、447.2±2.1和91.7±1.8μg/mL）。透射电子显微镜显示，[具体化合物1]破坏了TMV的颗粒形态，微量热泳动（MST）表明[具体化合物1]与CP结合，解离常数（Kd）为9.7±1.7μM。然后，分子对接和MST进一步表明[具体化合物1]与TMV突变蛋白的结合亲和力较弱（Kd = 561.3±83.2μM）。因此，我们推断二硫缩醛衍生物[具体化合物1]可能通过结合TMV CP来抑制TMV活性。这项工作为新型抗TMV药物的设计和优化提供了一些新的见解。
