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. A successful solution of the X-ray crystal structure of TLR8
in complex with TH1027 provided an in-depth mechanistic
insight into its binding mode, validating that TH1027 was located between two TLR8 monomers and recognized as an unconventional
pocket, thereby preventing TLR8 from activation. Further biological
evaluations showed that TH1027 dose-dependently suppressed
the TLR8-mediated inflammatory responses in both human monocyte cell
lines, peripheral blood mononuclear cells, and rheumatoid arthritis
patient specimens, suggesting a strong therapeutic potential against
autoimmune diseases.