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Co‐administration of Antimicrobial Peptides Enhances Toll‐like Receptor 4 Antagonist Activity of a Synthetic Glycolipid
Author(s) -
Facchini Fabio A.,
Coelho Helena,
Sestito Stefania E.,
Delgado Sandra,
Minotti Alberto,
Andreu David,
JiménezBarbero Jesús,
Peri Francesco
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700694
Subject(s) - tlr4 , cathelicidin , chemistry , lipopolysaccharide , peptide , agonist , receptor , melittin , antimicrobial peptides , lipid a , biochemistry , pharmacology , biology , immunology
This 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.