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.

Ciaramelli, C., Calabrese, V., Sestito, S., Pérez Regidor, L., Klett, J., Oblak, A., et al. (2016). Glycolipid-based TLR4 Modulators and Fluorescent Probes: Rational Design, Synthesis, and Biological Properties. CHEMICAL BIOLOGY & DRUG DESIGN, 88(2), 217-229 [10.1111/cbdd.12749].

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

CIARAMELLI, CARLOTTA
Primo
;
CALABRESE, VALENTINA
Secondo
;
SESTITO, STEFANIA ENZA;PIAZZA, MATTEO;PERI, FRANCESCO
Ultimo
2016

Abstract

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.
Articolo in rivista - Articolo scientifico
antagonists; computational chemistry; fluorescent chemical probes; glycolipids; HEK-TLR4 cells; MD-2; medicinal chemistry; TLR4;
antagonists; computational chemistry; fluorescent chemical probes; glycolipids; HEK-TLR4 cells; MD-2; medicinal chemistry; TLR4; Animals; Cell Line; Fluorescent Dyes; Glycolipids; Humans; Mice; Toll-Like Receptor 4; Drug Design; Biochemistry; Molecular Medicine
English
2016
88
2
217
229
reserved
Ciaramelli, C., Calabrese, V., Sestito, S., Pérez Regidor, L., Klett, J., Oblak, A., et al. (2016). Glycolipid-based TLR4 Modulators and Fluorescent Probes: Rational Design, Synthesis, and Biological Properties. CHEMICAL BIOLOGY & DRUG DESIGN, 88(2), 217-229 [10.1111/cbdd.12749].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/152473
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