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

  • Eur J Med Chem. 2025 May 8:293:117717. doi: 10.1016/j.ejmech.2025.117717.
Renjie Lin  1 ,  Jiajia Han  2 ,  Yun He  1 ,  Lin Xie  1 ,  Tianyu Gao  1 ,  Yaoming Chen  1 ,  Ye Zhong  3 ,  Qiang Ding  4 ,  Kui Cheng  5 ,  Xingang Yao  6 ,  Zhipeng Chen  7
Affiliations
  • 1. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3. School of Chemistry and Materials Science, Guangdong University of Education, Guangzhou, 510515, China.
  • 4. Center for Infection Biology, School of Medicine, Tsinghua University, Beijing, 100084, China.
  • 5. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 7. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 40344737 DOI: 10.1016/j.ejmech.2025.117717
Abstract

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.

Keywords
Antiviral; DENV-2; STAT2; ZIKV.
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