Discovery of Novel Isoxazole-Based Small-Molecule Toll-Like Receptor 8 Antagonists

Toll-like receptor 8 (TLR8) recognizes viral and bacterial
RNA,
initiating inflammatory responses that are crucial for innate immunity.
Dysregulated TLR8 signaling contributes to autoimmune diseases, including
systemic lupus erythematosus and rheumatoid arthritis, driving chronic
inflammation and tissue damage. Therefore, targeting TLR8 has gained
attention as a promising therapeutic strategy. We report a novel selective
TLR8 antagonist scaffold identified through computational modeling
and simulation. In silico-guided rational drug design and synthesis
led to potent isoxazole-based compounds that were characterized by
structure–activity relationships. The most active compounds
inhibited TLR8-mediated signaling in cell lines and primary cells,
reduced MyD88 recruitment, suppressed NF-κB- and IRF-dependent
signaling, and decreased inflammatory responses. In silico and pharmacological
analyses demonstrated competitive binding to the pocket of chemical
ligands within the TLR8 dimerization interface. These highly selective
and potent TLR8 antagonists possess favorable physicochemical properties,
representing potential clinical candidates for TLR8-targeted therapy.