Rationally designed small-molecule inhibitors targeting an unconventional pocket on the TLR8 protein-protein interface.

Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, TH1027 was identified as a highly potent and specific inhibitor of TLR8. Successful solution of the X-ray crystal structure of TLR8 in complex with TH1027 shed in-depth mechanistic insight of its binding mode, validating that TH1027 located between two TLR8 monomers and recognized an unconventional pocket thereby preventing TLR8 from activation. Further biological evaluations showed that TH1027 dose-dependently suppressed the TLR8-mediated inflammation responses in both human monocyte cell lines, peripheral blood mononuclear cells (PBMCs), and rheumatoid arthritis patient specimens, suggesting strong therapeutic potential against autoimmune diseases.