TH 1020 is a Toll-like receptor 5 (TLR5)/flagellin complex antagonist with an IC50 value of 0.85μM[1]. TH 1020 can inhibit flagellin-induced TLR5 signaling, but is ineffective against TLR2, TLR3, TLR4, TLR7, and TLR8[2]. TH 1020 inhibits downstream signaling by binding to the molecular interface between TLR5 dimers, disrupting the formation of functional tetramer complexes[3]. TH 1020 can inhibit TLR5 signaling in CD8+ T cells[4].
In vitro, pretreatment of IPEC-J2 cells infected with enterotoxigenic Escherichia coli (ETEC) strain C83901 with TH 1020 (1.5μM) for 2h completely inhibited the secretion of intracellular IL-17C[5]. Treatment of primary peripheral blood mononuclear cells (PBMCs) with TH 1020 (0.75, 1.5μM) significantly reduced the production of nitric oxide (NO) induced by flagellin and high mobility group protein B1 (HMGB1)[6].
In vivo, intraperitoneal injection of TH 1020 (100μg) for 4 days in ovarian cancer model mice significantly reduced the number of CCR2+ Ly6C+ cells in the tumor microenvironment and the total number of tumor-infiltrating macrophages[7].
References:
[1] Patra M C, Choi S. Recent progress in the development of Toll-like receptor (TLR) antagonists[J]. Expert opinion on therapeutic patents, 2016, 26(6): 719-730.
[2] Yan L, Liang J, Yao C, et al. Pyrimidine triazole thioether derivatives as Toll‐like receptor 5 (TLR5)/flagellin complex inhibitors[J]. ChemMedChem, 2016, 11(8): 822-826.
[3] Leifer C A, Medvedev A E. Molecular mechanisms of regulation of Toll-like receptor signaling[J]. Journal of Leucocyte Biology, 2016, 100(5): 927-941.
[4] Kang X, Liu C, Ding Y, et al. Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells[J]. Gut, 2023, 72(11): 2112-2122.
[5] Luo Y, Xu J, Zhang C, et al. Toll-like receptor 5-mediated IL-17C expression in intestinal epithelial cells enhances epithelial host defense against F4+ ETEC infection[J]. Veterinary research, 2019, 50(1): 48.
[6] Das N, Dewan V, Grace P M, et al. HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia[J]. Cell reports, 2016, 17(4): 1128-1140.
[7] Kolli S H, McGinty M T, Putelo A M, et al. Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands[J]. bioRxiv, 2025: 2025.06. 10.658497.
TH 1020是一种Toll样受体5（TLR5）/鞭毛蛋白复合物拮抗剂，IC50值为0.85μM[1]。TH 1020能够抑制鞭毛蛋白诱导的TLR5信号传导，对TLR2、TLR3、TLR4、TLR7和TLR8无效[2]。TH 1020通过结合TLR5二聚体之间的分子界面，破坏功能性四聚体复合物的形成，从而抑制下游的信号传导[3]。TH 1020能够抑制CD8+ T细胞中的TLR5信号传导[4]。
在体外，TH 1020（0.5μM）预处理产肠毒素大肠杆菌（ETEC）菌株C83901感染的IPEC-J2细胞2h，完全抑制了细胞内IL-17C的分泌[5]。TH 1020（0.75, 1.5μM）处理原代外周血单个核细胞（PBMC），显著减少了鞭毛蛋白和高迁移率族蛋白B1（HMGB1）诱导的一氧化氮（NO）的产生[6]。
在体内，TH 1020（100μg）通过腹腔注射处理卵巢癌模型小鼠4天，显著减少了肿瘤微环境中CCR2+ Ly6C+细胞，减少了肿瘤浸润巨噬细胞总数[7]。