Discovery of Dithioacetal Derivatives Containing Sulfonamide Moiety of Novel Antiviral Agents by TMV Coat Protein as a Potential Target
Yuyuan Yang, Jian Zhang, Xiangyang Li, Fangcheng He, Rong Wu, Deyu Hu, Baoan Song
Abstract
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 Y14, Y18, and Y21 exhibited excellent activities against TMV, with half-maximal effective concentrations (EC50) 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 Y14, Y18, and Y21, 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 d2 (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 Y21, and microscale thermophoresis (MST) showed that Y21 bonded to CP with a dissociation constant (Kd) of 9.7 ± 1.7 μM. Then, molecular docking and MST further illustrated that Y21 had a weak binding affinity with the TMV mutant protein (Kd = 561.3 ± 83.2 μM). Thus, we deduced that the dithioacetal derivative Y21 may inhibit TMV activity by binding TMV CP. This work provides some new insights for the design and optimization of novel anti-TMV agents.