Detalle de: Glycolipid‐based TLR 4 Modulators and Fluorescent Probes: Rational Design, Synthesis, and Biological Properties

The cationic glycolipid IAXO ‐102, a potent TLR 4 antagonist targeting both MD ‐2 and CD 14 co‐receptors, has been used as scaffold to design new potential TLR 4 modulators and fluorescent labels for the TLR 4 receptor complex (membrane TLR 4. MD ‐2 dimer and CD 14). The primary amino group of IAXO ‐102, not involved in direct interaction with MD ‐2 and CD 14 receptors, has been exploited to covalently attach a fluorescein (molecules 1 and 2 ) or to link two molecules of IAXO ‐102 through diamine and diammonium spacers, obtaining ‘dimeric’ molecules 3 and 4 . The structure‐based rational design of compounds 1‐4 was guided by the optimization of MD ‐2 and CD 14 binding. Compounds 1 and 2 inhibited TLR 4 activation, in a concentration‐dependent manner, and signaling in HEK ‐Blue TLR 4 cells. The fluorescent labeling of murine macrophages by molecule 1 was inhibited by LPS and was also abrogated when cell surface proteins were digested by trypsin, thus suggesting an interaction of fluorescent probe 1 with membrane proteins of the TLR 4 receptor system.