Jeong Uisuk, Lee Wang Hee, Choi Yang Seon, Haseeb Muhammad, Baek Wook-Young, Han Ji Hye, Choi Hongjoon, Kim Moon Suk, Suh Chang-Hee, Kim Wook, Choi Sangdun
S&K Therapeutics, Suwon, Korea.
Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
Exp Mol Med. 2025 Sep 1. doi: 10.1038/s12276-025-01526-w.
Endosomal Toll-like receptors (TLRs, including TLR3, TLR7, TLR8 and TLR9) play crucial roles in immune responses by recognizing pathogen-associated molecular patterns; however, their aberrant activation is implicated in inflammatory and autoimmune diseases. Developing endosomal TLR inhibitors against autoimmune diseases is clinically essential. Here we synthesized and optimized a series of compounds based on a candidate structure. The lead compounds, ETI41 and ETI60, potently inhibited endosomal TLR-mediated pro-inflammatory signaling with nanomolar activity in cellular, biophysical and in vivo assays. Both ETI41 and ETI60 selectively inhibited endosomal TLRs without affecting surface TLRs, as confirmed by immunoblotting and biophysical analyses. RNA sequencing revealed that these inhibitors modulated the expression of genes associated with inflammation. In vivo studies have shown that oral administration of ETI41 or ETI60 effectively ameliorates symptoms in mouse models of psoriasis, and systemic lupus erythematosus. These findings indicate that ETI41 and ETI60 hold significant potential as therapeutic agents for the treatment of autoimmune and inflammatory diseases through selective targeting of endosomal TLRs.
内体 Toll 样受体（TLRs，包括 TLR3、TLR7、TLR8 和 TLR9）通过识别病原体相关分子模式在免疫反应中发挥关键作用；然而，它们的异常激活与炎症和自身免疫性疾病有关。开发针对自身免疫性疾病的内体 TLR 抑制剂在临床上至关重要。在此，我们基于一个候选结构合成并优化了一系列化合物。先导化合物 ETI41 和 ETI60 在细胞、生物物理和体内试验中以纳摩尔活性有效抑制内体 TLR 介导的促炎信号传导。免疫印迹和生物物理分析证实，ETI41 和 ETI60 均选择性抑制内体 TLR，而不影响表面 TLR。RNA 测序显示，这些抑制剂调节了与炎症相关基因的表达。体内研究表明，口服 ETI41 或 ETI60 可有效改善银屑病和系统性红斑狼疮小鼠模型的症状。这些发现表明，ETI41 和 ETI60 通过选择性靶向内体 TLR，作为治疗自身免疫性和炎症性疾病的治疗剂具有巨大潜力。
