title: Pyrimidine Triazole Thioether Derivatives as Toll-Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors.
abstract: 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-α 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.
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Liang
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Chengbo
authors.initials: C
authors.lastname: Yao
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Peiyao
authors.initials: P
authors.lastname: Wu
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China. yin_hang@tsinghua.edu.cn.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D004305:Dose-Response Relationship, Drug; D005408:Flagellin / Q000737:chemistry / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D051198:Toll-Like Receptor 5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D011743:Pyrimidines; D054852:Small Molecule Libraries; D013440:Sulfides; C000612980:TH1020; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D014230:Triazoles; D005408:Flagellin
keywords: flagellin; immunomodulators; inhibitors; protein-protein interactions; toll-like receptor 5 (TLR5)