Molecular mapping and detoxification of the lipid A binding site by synthetic peptides.
Endotoxin [lipopolysaccharide (LPS)], the major antigen of the outer membrane of Gram-negative bacteria, consists of a variable-size carbohydrate chain that is covalently linked to N,O-acylated beta-1,6-D-glucosamine disaccharide 1,4'-bisphosphate (lipid A). The toxic activity of LPS resides in the lipid A structure. The structural features of synthetic peptides that bind to lipid A with high affinity, detoxify LPS in vitro, and prevent LPS-induced cytokine release and lethality in vivo were defined. The binding thermodynamics were comparable to that of an antigen-antibody reaction. Such synthetic peptides may provide a strategy for prophylaxis and treatment of LPS-mediated diseases.
Rustici
A
A
Biosynth Research Laboratories, Siena, Italy.
Velucchi
M
M
Faggioni
R
R
Sironi
M
M
Ghezzi
P
P
Quataert
S
S
Green
B
B
Porro
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001886:Bordetella pertussis / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008033:Limulus Test; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011112:Polymyxin B / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013696:Temperature
D008050:Lipid A; D008070:Lipopolysaccharides; D008823:Micelles; D010455:Peptides; D011112:Polymyxin B