We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells. Moreover, guanidinocalixarenes also inhibited TLR4 signaling when TLR4 was activated by a non-LPS stimulus, the plant lectin PHA. While the activity of guanidinocalixarenes in inhibiting LPS toxic action has previously been related to their capacity to bind LPS, we suggest a direct antagonist effect of calixarenes on TLR4/MD-2 dimerization, pointing at the calixarene moiety as a potential scaffold for the development of new TLR4-directed therapeutics.

Sestito, S., Facchini, F., Morbioli, I., Billod, J., Martin Santamaria, S., Casnati, A., et al. (2017). Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)-and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling. JOURNAL OF MEDICINAL CHEMISTRY, 60(12), 4882-4892 [10.1021/acs.jmedchem.7b00095].

Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)-and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling

SESTITO, STEFANIA ENZA
Primo
;
FACCHINI, FABIO ALESSANDRO
Secondo
;
PERI, FRANCESCO
Ultimo
2017

Abstract

We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells. Moreover, guanidinocalixarenes also inhibited TLR4 signaling when TLR4 was activated by a non-LPS stimulus, the plant lectin PHA. While the activity of guanidinocalixarenes in inhibiting LPS toxic action has previously been related to their capacity to bind LPS, we suggest a direct antagonist effect of calixarenes on TLR4/MD-2 dimerization, pointing at the calixarene moiety as a potential scaffold for the development of new TLR4-directed therapeutics.
Articolo in rivista - Articolo scientifico
TLR4, calixarenes, LPS, lectin
English
4882
4892
11
Sestito, S., Facchini, F., Morbioli, I., Billod, J., Martin Santamaria, S., Casnati, A., et al. (2017). Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)-and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling. JOURNAL OF MEDICINAL CHEMISTRY, 60(12), 4882-4892 [10.1021/acs.jmedchem.7b00095].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/153165
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