Epoxydicoumarin Derivative is a Novel Non-Nucleoside TLR8 Agonist: Screening, Synthesis and Biological Evaluation

Abstract

Toll-like receptors (TLRs) activate host innate immunity by recognizing microbial ligands and viral nucleic acids. Of late, TLR8 has emerged as an attractive target for antiviral activity, antitumor activity and vaccine development owing to its ability to recognize small synthetic molecules that induce pro-inflammatory cytokines, type 1 interferons and chemokines. Of the many synthetic and natural ligands researched so far, ligands derived from coumarin have been known to have enhanced antiviral and immunomodulatory properties. Thus, the coumarin scaffold plays an important role through the modulation of cytokines by noncovalent interactions with various enzymes and receptors. The present study aims to identify a coumarin derivative that binds to the TLR8 receptor and induce NF-κB activity. In silico screening and chemical synthesis were performed to realize novel coumarin leads with potential TLR8 agonistic activity. HEK-Blue™ hTLR8 cell line was used to validate the TLR8 agonist evaluation In vitro. The key finding of this study brings out strong evidence supporting the binding of the 3,31-(411-N,N-dimethylaminophenylmethylene)-4,41-epoxydicoumarin to TLR8 receptor in comparison to the co-crystallized R848 ligand.