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

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

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: chengk@smu.edu.cn.
  • 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: yaoxingang@smu.edu.cn.
  • 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: czpwyq@smu.edu.cn.
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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