TY - JOUR
T1 - Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor 4 Antagonist Activity of a Synthetic Glycolipid
AU - Facchini, Fabio A.
AU - Coelho, Helena
AU - Sestito, Stefania E.
AU - Delgado, Sandra
AU - Minotti, Alberto
AU - Andreu, David
AU - Jiménez-Barbero, Jesús
AU - Peri, Francesco
N1 - This study was financially supported by the H2020-MSC-ETN-642157 project TOLLerant. The Italian Ministry for Foreign Affairs and International Cooperation (MAECI) is acknowledged. Work at Pompeu Fabra University was supported by MINECO (grants SAF2011-24899, AGL2014-52395-C2-2-R to D.A., CTQ2015-64597-C2-1-P and MINECO-Severo Ochoa Excellence Acreditation 2017-2021 (SEV-2016-0644) to J.J.-B.) with FEDER funds, and by Generalitat de Catalunya (2014SGR692).
PY - 2018/2/6
Y1 - 2018/2/6
N2 - 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.
AB - 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.
KW - aggregation
KW - antimicrobial peptides
KW - FP7
KW - small-molecule antagonists
KW - toll-like receptor 4
UR - http://www.scopus.com/inward/record.url?scp=85040863256&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201700694
DO - 10.1002/cmdc.201700694
M3 - Article
C2 - 29265636
AN - SCOPUS:85040863256
VL - 13
SP - 280
EP - 287
JO - Chemmedchem
JF - Chemmedchem
SN - 1860-7179
IS - 3
ER -