Design, synthesis and biological evaluation of dapsone derivatives with broad-spectrum antiviral activity.

Inhibition of STAT2 degradation has emerged as a promising strategy for flaviviruses. The NS5 protein of the ZIKV and DENV-2 inhibits the IFN-Ⅰ antiviral response by degrading STAT2, thereby evading the host's immune defense. Therefore, the development of novel agents capable of inhibiting STAT2 degradation via targeted modulation constitutes a pivotal therapeutic strategy for controlling viral infections. In this study, HEK293TSTAT2-mCherry-Flag/rtTA-HA-NS5 cells were used as reporter tools. Through screening the ZINC drug-like database, the lead compound ZINC000060514583 was obtained and structurally modified to yield the optimized compounds SMU-1k, which significantly inhibited the degradation of STAT2. We verified its activity against ZIKV and DENV-2 through Western blotting, RT-qPCR, plaque formation assays, and immunofluorescence experiments. The results showed that SMU-1k significantly inhibited the expression of NS5 protein and restored the level of STAT2 to a certain extent. Additionally, the EC50 values of SMU-1k against ZIKV and DENV-2 were 7.08 ± 0.06 μM and 3.96 ± 0.11 μM, respectively, which helped to alleviate the cytopathic effects caused by ZIKV and DENV-2 infection. Here, we have successfully characterized a novel small-molecule compound that selectively blocks STAT2 proteasomal degradation while exhibiting potent dual antiviral efficacy against both ZIKV and DENV-2, thereby revealing a promising lead candidate for developing broad-spectrum antiviral therapeutics.