2. Academic Validation
  3. Design, synthesis, and radioprotection activity evaluation of 1H-1,2,3-triazole derivatives as TLR2/1 small molecule agonists

Design, synthesis, and radioprotection activity evaluation of 1H-1,2,3-triazole derivatives as TLR2/1 small molecule agonists

  • Bioorg Med Chem Lett. 2026 Aug:137:130657. doi: 10.1016/j.bmcl.2026.130657.
Hao Wang 1,  Xinru Liu 2,  Wenteng Zheng 3,  Jing Xu 2,  Shuchen Liu 4,  Shouguo Zhang 5,  Lin Wang 6,  Tao Peng 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
  • 2 Beijing Institute of Radiation Medicine, Beijing, 100850, PR China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 4 Beijing Institute of Radiation Medicine, Beijing, 100850, PR China. Electronic address: liusc118@sohu.com.
  • 5 Beijing Institute of Radiation Medicine, Beijing, 100850, PR China. Electronic address: zhangshouguo1409@sina.com.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Beijing Institute of Radiation Medicine, Beijing, 100850, PR China. Electronic address: wanglin@bmi.ac.cn.
  • 7 Beijing Institute of Radiation Medicine, Beijing, 100850, PR China. Electronic address: pengtao_3@sina.com.
PMID: 41974286 DOI: 10.1016/j.bmcl.2026.130657
Abstract

Toll-like receptors (TLRs), a family of Pattern Recognition Receptors of the innate immune system, have been shown to exert radioprotective effects by activating the NF-κB signaling pathway. In this context, we designed and synthesized a series of novel TLR2/1 small molecule agonists, 1H-1,2,3-triazole derivatives, to evaluate their radioprotective activity, with compound H9 exhibiting the most potent radiation-protective effect.H9 showed significant radioprotective effects in mice irradiated with 8.5 Gy of 60Co γ rays. The survival rates of the 80 mg/kg and 60 mg/kg H9-treated groups were both 100%. Furthermore, H9 can accelerate the recovery of peripheral blood cells in irradiated mice. The ELISA experiment showed that the levels of the antiradiation cytokine biomarker G-CSF were significantly increased in the serum of irradiated mice after treatment with H9. In human TLR2 and TLR1 transiently cotransfected HEK 293 T cells., H9 exhibits significant TLR2/1 agonist activity. Immunoprecipitation and cellular thermal shift assays (CETSA) confirmed that H9 targets the TLR2/1 rather than TLR2/6 heterodimeric complex. Summary: We demonstrated that H9 is a novel TLR2/1 agonist with significant efficacy in acute radiation protection, indicating that TLR2/1 small molecule agonists hold broad promise for applications in acute radioprotection.

Keywords

1H-1,2,3-triazoles; Agonist; Radioprotection; Toll-like receptor.

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