Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain
Copyright policy )Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain
SignificanceExcess Toll-like receptor 2 (TLR2) signaling has been implicated in numerous inflammatory diseases, yet there is no TLR2 inhibitor licensed for human use. Using computer-aided drug design (CADD), we identified a compound, C16H15NO4(C29), and a derivative,ortho-vanillin, that inhibit TLR2 signaling in vitro and in vivo. Our findings also revealed unexpected differences between TLR2/1 and TLR2/6 signaling in mice vs. humans. Importantly, our data provide proof of principle that the CADD-targeted BB loop pocket residues are critical for TLR2 signaling and may be targeted therapeutically.
- Case Western Reserve University United States
- University of Maryland, Baltimore United States
Inflammation, Interleukin-8, Anti-Inflammatory Agents, Drug Evaluation, Preclinical, Toll-Like Receptor 1, Antioxidants, Toll-Like Receptor 2, Protein Structure, Tertiary, Mice, HEK293 Cells, Toll-Like Receptor 6, Benzaldehydes, Drug Design, Animals, Humans, RNA, Messenger, Signal Transduction
Inflammation, Interleukin-8, Anti-Inflammatory Agents, Drug Evaluation, Preclinical, Toll-Like Receptor 1, Antioxidants, Toll-Like Receptor 2, Protein Structure, Tertiary, Mice, HEK293 Cells, Toll-Like Receptor 6, Benzaldehydes, Drug Design, Animals, Humans, RNA, Messenger, Signal Transduction
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