title: Development of C5a receptor antagonists. Differential loss of functional responses.
abstract: C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.
authors.affiliation: Department of Analytical Biochemistry, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Z D
authors.initials: ZD
authors.lastname: Konteatis
authors.forename: S J
authors.initials: SJ
authors.lastname: Siciliano
authors.forename: G
authors.initials: G
authors.lastname: Van Riper
authors.forename: C J
authors.initials: CJ
authors.lastname: Molineaux
authors.forename: S
authors.initials: S
authors.lastname: Pandya
authors.forename: P
authors.initials: P
authors.lastname: Fischer
authors.forename: H
authors.initials: H
authors.lastname: Rosen
authors.forename: R A
authors.initials: RA
authors.lastname: Mumford
authors.forename: M S
authors.initials: MS
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D015936:Complement C5a / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding
chemical_list: D010446:Peptide Fragments; D015936:Complement C5a; D009195:Peroxidase; D020558:GTP Phosphohydrolases; D002118:Calcium