Selective hexapeptide agonists and antagonists for human complement C3a receptor

Scully, Conor C. G., Blakeney, Jade S., Singh, Ranee, Hoang, Huy N., Abbenante, Giovanni, Reid, Robert C. and Fairlie, David P. (2010) Selective hexapeptide agonists and antagonists for human complement C3a receptor. Journal of Medicinal Chemistry, 53 13: 4938-4948. doi:10.1021/jm1003705

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Author Scully, Conor C. G.
Blakeney, Jade S.
Singh, Ranee
Hoang, Huy N.
Abbenante, Giovanni
Reid, Robert C.
Fairlie, David P.
Title Selective hexapeptide agonists and antagonists for human complement C3a receptor
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2010-07-08
Year available 2010
Sub-type Article (original research)
DOI 10.1021/jm1003705
Volume 53
Issue 13
Start page 4938
End page 4948
Total pages 11
Editor Philip S. Portoghese
Place of publication Washington, DC, U.S.A.
Publisher American Chemical Society
Collection year 2011
Language eng
Formatted abstract
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 125I-labeled C3a to human macrophages, 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 β-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.
© 2010 American Chemical Society.
Keyword Nuclear-magnetic-resonance
Th2 effector functions
Anaphylatoxin C3a
Human C5a
Polymorphonuclear leukocytes
Decapeptide agonists
Cyclic antagonists
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 14 times in Scopus Article | Citations
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Created: Sun, 18 Jul 2010, 00:04:04 EST