Utilization of sialic acid-binding synthetic peptide sequences derived from pertussis toxin as novel anti-inflammatory agents.
Pertussis toxin, a virulence factor produced by the organism Bordetella pertussis, has been shown to have functional similarities with selectins and to bind to similar sialic acid-containing oligosaccharides structures. Previously, we demonstrated that the amino-terminal region of the S2 subunit of pertussis toxin contained a short six amino acid sequence (SPYGRC) which displayed reasonable homology to a sequence that constitutes a portion of the sialic acid binding site in wheat germ agglutinin. Synthetic peptides containing this hexapeptide motif had the ability to bind to sialic acid-containing glycoconjugates including the putative oligosaccharide receptors (sialyl Lewis X and sialyl Lewis A) for selectins. Control peptides containing randomized sequences were inactive at inhibiting binding, indicating that the hexapeptide motif is important for interacting with sialic acid. Since pertussis toxin-derived peptides demonstrated the ability to interact with selectin receptors, we speculated that they should antagonize selectin-mediated inflammatory activity. To test this hypothesis, we evaluated the peptides for the ability to reduce neutrophil binding to activated endothelial cells as well as the anti-inflammatory activity in the mouse footpad swelling assay. Both S2 peptides were active at reducing neutrophil binding and footpad swelling, while the randomized control peptides were inactive.
Heerze
L D
LD
Department of Medical Microbiology and Infectious Diseases, University of Alberta, Edmonton, Canada.
Smith
R H
RH
Wang
N
N
Armstrong
G D
GD
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001667:Binding, Competitive; D001710:Biotin; D002240:Carbohydrate Sequence; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006001:Glycoconjugates / Q000737:chemistry / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D037342:Pertussis Toxin; D019087:Selectins / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000737:chemistry* / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006001:Glycoconjugates; D037102:Lectins; D010446:Peptide Fragments; D019087:Selectins; D012794:Sialic Acids; D010566:Virulence Factors, Bordetella; D000509:alpha-Fetoproteins; D012710:Serum Albumin, Bovine; D001710:Biotin; D037342:Pertussis Toxin; D019158:N-Acetylneuraminic Acid