Development of C5a receptor antagonists. Differential loss of functional responses.
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.
Konteatis
Z D
ZD
Department of Analytical Biochemistry, Merck Research Laboratories, Rahway, NJ 07065.
Siciliano
S J
SJ
Van Riper
G
G
Molineaux
C J
CJ
Pandya
S
S
Fischer
P
P
Rosen
H
H
Mumford
R A
RA
Springer
M S
MS
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
D010446:Peptide Fragments; D015936:Complement C5a; D009195:Peroxidase; D020558:GTP Phosphohydrolases; D002118:Calcium