Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors

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• 作者：Lei Yan ; Jiaqi Liang ; Chengbo Yao ; Peiyao Wu ; Xianfeng Zeng ; Dr. Kui Cheng and Prof. Dr. Hang Yin
• 关键词：flagellin ; immunomodulators ; inhibitors ; protein&ndash ; protein interactions ; toll-like receptor 5 (TLR5)
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：April 19, 2016
• 年：2016
• 卷：11
• 期：8
• 页码：822-826
• 全文大小：1898K
• ISSN：1860-7187

文摘

Protein–protein interactions have been regarded as “undruggable” despite their importance in many biological processes. The complex formed between host toll-like receptor 5 (TLR5) and flagellin, a globular protein that is the main component of a bacterial flagellum, plays a vital role in a number of pathogen defenses, immunological diseases and cancers. Through high-throughput screening, we identified two hits with a common pharmacophore, which were used to successfully develop a series of small-molecule probes as novel inhibitors of flagellin binding to TLR5. In a multitude of assays, 4-((4-benzyl-5-(pyridin4yl)-4H-1,2,4-triazol-3-yl)thio)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine (TH1020) was identified as a potent antagonist of TLR5 signaling with promising activity (IC₅₀=0.85±0.12 μm) and specificity. Furthermore, TH1020 was shown to repress the expression of downstream TNF- signaling pathways mediated by the TLR5/flagellin complex formation. Based on molecular docking simulation, TH1020 is suggested to compete with flagellin and disrupt its association with TLR5. TH1020 provides a much-needed molecular probe for studying this important protein–protein interaction and a lead compound for identifying novel therapeutics targeting TLR5.