Glycolipid-based TLR4 Modulators and Fluorescent Probes: Rational Design, Synthesis, and Biological Properties Articles uri icon


  • Ciaramelli, C.
  • Calabrese, V.
  • Sestito, S.E.
  • Pérez-Regidor, L.
  • Oblak, A.
  • Jerala, R.
  • Piazza, M.
  • Martín-Santamaría, S.
  • Peri, F.

publication date

  • January 2016

start page

  • 217

end page

  • 229


  • 2


  • 88

International Standard Serial Number (ISSN)

  • 17470277 (ISSN)


  • The cationic glycolipid IAXO‐102, a potent TLR4 antagonist targeting both MD‐2 and CD14 co‐receptors, has been used as scaffold to design new potential TLR4 modulators and fluorescent labels for the TLR4 receptor complex (membrane TLR4.MD‐2 dimer and CD14). The primary amino group of IAXO‐102, not involved in direct interaction with MD‐2 and CD14 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 CD14 binding. Compounds 1 and 2 inhibited TLR4 activation, in a concentration‐dependent manner, and signaling in HEK‐Blue TLR4 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 TLR4 receptor system.


  • antagonists; computational chemistry; fluorescent chemical probes; glycolipids; hek‐tlr4 cells; md‐2; medicinal chemistry; tlr4