Inhibition of LPS-responses by synthetic peptides derived from LBP associates with the ability of the peptides to block LBP-LPS interaction.
The ability of LPS-binding protein (LBP) to greatly potentiate cell responses to lipopolysaccharide (LPS) may largely contribute to LPS toxicity in sepsis. The study of agents with the capacity to block the interaction between LBP and LPS might improve the understanding of the role of LBP in Gram-negative infections as well as offering new therapeutic tools for septic disorders. Here we confirm the ability of synthetic peptides comprising the human LBP amino acid region 86-108 to interfere with the LBP-LPS interaction. The analysis of selected alanine mutants of a blocking peptide corresponding to the LBP region 86-99 suggests the importance of peptide amphipathicity for the inhibitory activity. The potency of the native peptide and a selected analogue at inhibiting in vitro and in vivo LPS-induced responses was associated with their relative activity in blocking LBP-LPS interaction. It was remarkable that these peptides were at least 500-fold more active in vivo than in vitro. Also, the inhibitory activity of peptides LBP86-99 and LBPK95A seems to be independent of LBP concentrations, a behavior that may be relevant for the potential use of these peptides in septic disorders where LBP serum concentrations are considerably elevated.
Araña
Manuel de J
Mde J
Division of Chemistry & Physics, Center for Genetic Engineering and Biotechnology, La Habana, Cuba. manuel.arana@cigb.edu.cu
Vallespi
Maribel G
MG
Chinea
Glay
G
Vallespi
Guillermo V
GV
Rodriguez-Alonso
Ingrid
I
Garay
Hilda E
HE
Buurman
Wim A
WA
Reyes
Osvaldo
O
D000209:Acute-Phase Proteins; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D008136:Longevity / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000276:immunology; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D013329:Structure-Activity Relationship; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010455:Peptides; D000099231:Lipopolysaccharide-Binding Protein