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Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

2015; National Academy of Sciences; Volume: 112; Issue: 17 Linguagem: Inglês

10.1073/pnas.1422576112

1091-6490

Pragnesh Mistry, Michelle Laird, Ryan S. Schwarz, Shannon N. Greene, Tristan Dyson, Greg A. Snyder, Tsan Sam Xiao, Jay Chauhan, Steven Fletcher, Vladimir Y. Toshchakov, Alexander D. MacKerell, Stefanie N. Vogel,

Antimicrobial Peptides and Activities

Significance Excess 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, C 16 H 15 NO 4 (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.