Facchini, Fabio A.Coelho, HelenaSestito, Stefania EnzaDelgado, SandraMinotti, AlbertoAndreu Martínez, DavidJiménez-Barbero, Jesús J.Peri, Francesco2018-04-122018-04-122018Facchini FA, Coelho H, Sestito SE, Delgado S, Minotti A, Andreu D et al. Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor 4 Antagonist Activity of a Synthetic Glycolipid. ChemMedChem. 2018 Feb 6;13(3):280-7. DOI: 10.1002/cmdc.2017006941860-7179http://hdl.handle.net/10230/34344This study examines the effect of co-administration of antimicrobial peptides and the synthetic glycolipid FP7, which is active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two lipopolysaccharide (LPS)-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, because it also occurs if cells are stimulated by the plant lectin phytohemagglutinin, a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on the LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of the TLR4 response.application/pdfeng© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/cmdc.201700694FP7AggregationAntimicrobial peptidesSmall-molecule antagonistsToll-like receptor 4info:eu-repo/semantics/openAccess