Pepper Mild Mottle Virus Coat Protein as a Novel Target to Screen Antiviral Drugs.

Pepper mild mottle virus (PMMoV) has caused serious economic losses to crop production in many countries. The coat protein (CP) of PMMoV is a multifunctional protein proved to be a determining factor in the assignment of virulence type. Therefore, we studied the interaction between drugs and PMMoV CP as a method to screen anti-PMMoV agents. In this study, vanisulfane (6f) exhibited good inactivation activity (68.5%) by biological activity screening. Meanwhile, the green fluorescent protein and PMMoV CP expression changes of vanisulfane against PMMoV were verified by western blot and qRT-PCR experiments. The affinity between vanisulfane and PMMoV CP was predicted to be the best by autodocking and molecular dynamics simulation. PMMoV CP was purified for the first time from the soluble fraction, and the strong affinity between vanisulfane and CP was further verified by interaction experiments. Therefore, this study found that vanisulfane is a potential anti-PMMoV drug targeting PMMoV CP.

Design, Synthesis, Anti-Tomato Spotted Wilt Virus Activity, and Mechanism of Action of Thienopyrimidine-Containing Dithioacetal Derivatives.

Currently, there is insufficient viricide to effectively control tomato spotted wilt virus (TSWV). To address this pending issue, a series of thienopyrimidine-containing dithioacetal derivatives were prepared and tested for their anti-TSWV activities. A subsequent three-dimensional quantitative structure-activity relationship was constructed to indicate the development of optimal compound 35. The obtained compound 35 had excellent anti-TSWV curative, protective, and inactivating activities (63.0, 56.6, and 74.1%, respectively), and the EC50 values of protective and inactivating activities of compound 35 were 252.8 and 113.5 mg/L, respectively, better than those of ningnanmycin (284.8 and 144.7 mg/L) and xiangcaoliusuobingmi (624.9 and 300.0 mg/L). In addition, the anti-TSWV activity of compound 35 was associated with defense-related enzyme activities, enhanced photosynthesis, and reduced stress response, thereby enhancing disease resistance.

Design, synthesis, anti-TMV activity, and preliminary mechanism of cinnamic acid derivatives containing dithioacetal moiety.

A series of cinnamic acid derivatives, which contained dithioacetal moiety, were designed and synthesized, and their anti-plant virus activity against Tobacco mosaic virus (TMV) were evaluated. Most target compounds exhibited good anti-plant virus activities. Compound 2y, especially at 500 mg/L concentration, had an excellent activity against TMV, and its curative, protective, and inactivating activities were 62.5%, 61.8%, and 83.5%, respectively. These activity values were significantly superior to those of ribavirin (45.9%, 39.8%, and 70.3%) and xiangcaoliusuobingmi (44.7%, 48.3%, and 71.7%) and comparable to those of ningnanmycin (61.9%, 53.3%, and 85.2%). Compound 2y presented an EC50 value of 50.7 mg/L for inactivating activity against TMV, which was superior to those of ningnanmycin (51.5 mg/L), ribavirin (160.4 mg/L), and xiangcaoliusuobingmi (83.0 mg/L). Through transmission electron microscopy, we found that compound 2y caused a certain degree of damage to TMV particles, which caused them to break and bend. Four conventional hydrogen bonds were formed with amino acid residues GLN34, THR37, ARG90, and ARG46 of TMV coat protein (CP) through molecular docking. Microscale thermophoresis test results showed that compound 2y with TMV CP had a strong binding force, and the dissociation constant (Kd) was 1.6 µM. In summary, the cinnamic acid derivatives containing dithioacetal moiety provide a foundation for further research on antiviral agents.

Design, synthesis, bioactivity and mechanism of dithioacetal derivatives containing dioxyether moiety.

The present work designed and synthesized a series of dithioacetal derivatives containing dioxyether, as well as evaluated their antiviral activities against tobacco mosaic virus (TMV). Bioassays demonstrated that the target compounds showed excellent anti-TMV activities in vivo and in vitro. Compound 24c has excellent anti-TMV activities, and its curative, protective and inactivating activities for TMV were 50.9%, 58.9% and 81.8%, respectively, which are obviously superior to those of ribavirin (50.2%, 41.3% and 69.5%, respectively). Moreover, the EC50 of the inactivating activities of the anti-TMV of compound 24c is 67.9 mg/L, which is superior to that of ribavirin (149.5 mg/L). Transmission electron microscopy showed that compound 24c caused great damage to the morphology of TMV particles, causing fracture and bending. Molecule docking model revealed that this compound formed five conventional hydrogen bonds with the active sites of amino acids GLN57, ASN73, TYR139, and SER138. Furthermore, the test results of Fluorescence titration and microscale thermophoresis showed that compound 24c has a strong binding force with TMV coat protein (TMV CP), with an association constant (Ka) of 1.04 × 105 L/mol and dissociation constant (Kd) of 1.6 ±â€¯0.6 µM. These results indicate that the dithioacetal derivatives containing dioxyether are worthy of further research and development as novel antiviral agents.

Design, Synthesis, Antiviral Bioactivity, and Defense Mechanisms of Novel Dithioacetal Derivatives Bearing a Strobilurin Moiety.

A series of dithioacetal derivatives bearing a strobilurin moiety were designed and synthesized on the basis of our previous work. The antiviral activities of these compounds against Potato virus Y (PVY), Cucumber mosaic virus (CMV), and Tobacco mosaic virus (TMV) were systematically evaluated. Bioassay results indicated that C14 elicited excellent curative and protective activities against PVY, CMV, and TMV. The former had 50% effective concentrations (EC50) of 125.3, 108.9, and 181.7 µg/mL, respectively, and the latter had 148.4, 113.2, and 214.6 µg/mL, respectively, which were significantly superior to those of lead compound 6f (297.6, 259.6, and 582.4 µg/mL and 281.5, 244.3, and 546.3 µg/mL, respectively), Ningnanmycin (440.5, 549.1, and 373.8 µg/mL and 425.3, 513.3, and 242.7 µg/mL, respectively), Chitosan oligosaccharide (553.4, 582.8, and 513.8 µg/mL and 547.3, 570.6, and 507.9 µg/mL, respectively), and Ribavirin (677.4, 690.3, and 686.5 µg/mL and 652.7, 665.4, and 653.4 µg/mL, respectively). Moreover, defensive enzyme activities and RT-qPCR analysis demonstrated that the antiviral activity was associated with the changes of SOD, CAT, and POD activities in tobacco, which was proved by the related proteins of abscisic acid signaling pathway. This work provided a basis for further design, structural modification, and development of dithioacetal derivatives as new antiviral agents.