Discovery of ETI41 and ETI60: novel selective endosomal Toll-like receptor inhibitors for the treatment of autoimmune diseases.

ABSTRACT: Endosomal Toll-like receptors (TLRs, including TLR3, TLR7, TLR8 and TLR9) play crucial roles in immune responses by recognizing pathogen-associated molecular patterns; however, their aberrant activation is implicated in inflammatory and autoimmune diseases. Developing endosomal TLR inhibitors against autoimmune diseases is clinically essential. Here we synthesized and optimized a series of compounds based on a candidate structure. The lead compounds, ETI41 and ETI60, potently inhibited endosomal TLR-mediated pro-inflammatory signaling with nanomolar activity in cellular, biophysical and in vivo assays. Both ETI41 and ETI60 selectively inhibited endosomal TLRs without affecting surface TLRs, as confirmed by immunoblotting and biophysical analyses. RNA sequencing revealed that these inhibito

SUBMITTER: Jeong U 

PROVIDER: S-EPMC12508057 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature