ArticleProceedings of the National Academy of Sciences of the United States of America2015
Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
97 citing papers in PubMed, 170 citations in OpenAlex.
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- The role of toll-like receptors in tributyltin-, dibutyltin-, and pentachlorophenol-induced stimulation of tumor necrosis factor-alpha (TNFα) production in human immune cells.Archives of toxicology · 2026Article
- The Characterization of a New AG-II-like Glycoprotein fromCurrent issues in molecular biology · 2026Article
- Group B streptococcal membrane vesicles induce proinflammatory responses in neonatal meninges.Infection and immunity · 2026Article
- Postbiotics From Ligilactobacillus salivarius Enhance Mitochondrial Robustness Via TLR2 Signaling in Intestinal Macrophages.Probiotics and antimicrobial proteins · 2026Article
- Emerging host-directed strategies for overcoming drug resistance and immune evasion in Staphylococcus aureus infections.Journal of advanced research · 2026Review
- The contributions of TLR2, TLR8 and TLR3 to direct and antibody-dependent enhancement of dengue virus serotype 2 infection.Npj viruses · 2026Article
- Intestinal Epithelial-like Cells Stimulated by a Functional Food Ingredient Promote Lysyl Oxidase (LOX) Expression in Osteoblast Precursor Cells via BMP-1 Secretion.International journal of molecular sciences · 2026Article
- IntratumoralAnimals : an open access journal from MDPI · 2026Article
- Toll-like receptor 2 drives liver senescence and fibrosis in aging through gut-derived microbial signaling.Cellular & molecular biology letters · 2026Article
- The function of TLR2 and the microbiome in macrophage-dependent dissemination of nontuberculous mycobacterial gut infection.International journal of biological sciences · 2026Article
- Human neutrophils recognize group B streptococciFrontiers in immunology · 2026Article
- BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting innate immune sensors for therapeutic strategies in infectious diseases.Journal of microbiology (Seoul, Korea) · 2025Review
- Toll-Like Receptors in Pentachlorophenol- and Dibutyltin-Induced Production of Pro-Inflammatory Cytokines, Interleukin (IL)-1β, and IL-6, by Human Immune Cells.Journal of applied toxicology : JAT · 2025Article
- Immunostimulatory effects mechanism of polysaccharide extracted from Acanthopanax senticosus on RAW 264.7 cells through activating the TLR/MAPK/NF-κB signaling pathway.Scientific reports · 2025Article
- Fucosylated Glycosaminoglycan Oligosaccharide HS14, Derived from Sea Cucumbers, Is a Novel Inhibitor of Platelet Toll-like Receptor 2.Marine drugs · 2025Article
- The Possible Mechanistic Basis of Individual Susceptibility to Spike Protein Injury.Advances in virology · 2025Review
- Massively Parallel Screening of Toll/Interleukin-1 Receptor (TIR)-Derived Peptides Reveals Multiple Toll-Like Receptors (TLRs)-Targeting Immunomodulatory Peptides.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
37 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.