Selective hexapeptide agonists and antagonists for human complement C3a receptor.
Human anaphylatoxin C3a, formed through cleavage of complement protein C3, is a potent effector of innate immunity via activation of its G protein coupled receptor, human C3aR. Previously reported short peptide ligands for this receptor either have low potency or lack receptor selectivity. Here we report the first small peptide agonists that are both potent and selective for human C3aR, derived from structure-activity relationships of peptides based on the C-terminus of C3a. Affinity for C3aR was examined by competitive binding with (125)I-labeled C3a to human PBMCs [corrected], agonist versus antagonist activity measured using fluorescence detection of intracellular calcium, and general selectivity monitored by C3a-induced receptor desensitization. An NMR structure for an agonist in DMSO showed a beta-turn motif that may be important for C3aR binding and activation. Derivatization produced a noncompetitive and insurmountable antagonist of C3aR. Small molecule C3a agonists and antagonists may be valuable probes of immunity and inflammatory diseases.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Conor C G
CC
Scully
Jade S
JS
Blakeney
Ranee
R
Singh
Huy N
HN
Hoang
Giovanni
G
Abbenante
Robert C
RC
Reid
David P
DP
Fairlie
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011951:Receptors, Complement / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D020298:U937 Cells
D009842:Oligopeptides; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D002118:Calcium