Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a.
The synthesis and structure-activity relationships of C-terminal octapeptide analogues of anaphylatoxin C5a have been studied. The introduction of hydrophobic amino acids into the N-acetylated native octapeptide (N-Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) (1) has led to an analogue with 100 times more activity than the native octapeptide in inhibiting the binding of 125I-labeled anaphylatoxin C5a to human neutrophil membrane receptors. The observed apparent binding Ki's for the compounds (8-10) are in the range of 1-3 microM, and they possess nearly full agonist activity, despite the fact that these analogues are one-eighth or -ninth the size of the natural ligand anaphylatoxin C5a.
Kawai
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Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Quincy
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DA
Lane
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Mollison
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KW
Or
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Luly
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Carter
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D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015936:Complement C5a / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a