Toll-like receptors (TLRs) are highly conserved transmembrane proteins which detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). TLRs play a vital role in the innate immune system. Ten different kinds of TLRs (TLR1-10) have been identified in human. Among these, TLR7 and TLR8 both locate in the endosome, where they recognize viral ssRNA and synthetic tricyclic imidazoquinoline derivatives. Due to their phylogenetical and structural similarity, especially the sequence and structure homology, we have faced great challenges in the development of antagonists targeting TLR7 alone. In this study, we have discovered the first TLR7 small molecule antagonist S-38 (IC50 = 340 nM) with negligible cytotoxicity. In THP-1 cells, compound S-38 inhibited R848-induced production of the production of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in a dose-dependent manner. Moreover, in our test with clinical samples, S-38 also showed potent inflammation-suppressing activities by preventing the production of TNF-α in peripheral blood mononuclear cells (PBMCs) harvested from donors. In conclusion, we have successfully developed the first TLR7 small molecule antagonist which could be used as a chemical probe to understand the biological relevance of TLR7 in different pathogenesis processes. Our effort in the discovery of TLR7 antagonist may contribute to the development of novel therapeutic strategies for autoimmune diseases.

Discovery of novel toll-like receptor 7 antagonists

2019 Spring National Meeting

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