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

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.