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

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.