20.500.12556/RUL-176588 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. antagonists genetics peptides proteins receptors screening assays Tollu podoben receptor 8 antagonisti TLR8 izoksazol imunost tarčna zdravila true false true Angleški jezik Slovenski jezik Članek v reviji 2025-12-04 13:56:55 2025-12-04 13:57:02 2025-12-22 04:13:32 0000-00-00 00:00:00 2025 0 0 Str. 4888-4907 iss. 4 Vol. 68 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.2-021.321 1520-4804 10.1021/acs.jmedchem.4c03148 235973123 discovery-of-novel-isoxazole-based-small-molecule-toll-like-receptor-8-antagonists.pdf discovery-of-novel-isoxazole-based-small-molecule-toll-like-receptor-8-antagonists.pdf 1 C935DC4824C87127DEAA221A89B140C5 8945526eaa1133941769c4718e2909fe43b6e9a2585a2d75f45f02d0a298c795 c62dc92a-d110-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=223014 https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03148 0 56d283bd-d110-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=223013 Fakulteta za farmacijo 0 0 0