Potent cyclic antagonists of the complement C5a receptor on human polymorphonulcear leukocytes. Relationships between structures and activity

March, Darren R., Proctor, Lavinia M., Stoermer, Martin J., Sbaglia, Robert, Abbenante, Giovanni, Reid, Robert C., Woodruff, Trent M., Wadi, Khemar, Paczkowski, Natalii, Tyndall, Joel D. A., Taylor, Stephen M. and Fairlie, David P. (2004) Potent cyclic antagonists of the complement C5a receptor on human polymorphonulcear leukocytes. Relationships between structures and activity. Molecular Pharmacology, 65 4: 868-879. doi:10.1124/mol.65.4.868


Author March, Darren R.
Proctor, Lavinia M.
Stoermer, Martin J.
Sbaglia, Robert
Abbenante, Giovanni
Reid, Robert C.
Woodruff, Trent M.
Wadi, Khemar
Paczkowski, Natalii
Tyndall, Joel D. A.
Taylor, Stephen M.
Fairlie, David P.
Title Potent cyclic antagonists of the complement C5a receptor on human polymorphonulcear leukocytes. Relationships between structures and activity
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
Publication date 2004-01-01
Sub-type Article (original research)
DOI 10.1124/mol.65.4.868
Volume 65
Issue 4
Start page 868
End page 879
Total pages 12
Place of publication Bethesda, USA
Publisher American Soc Pharmacology Experimental Therapeutics
Collection year 2004
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
780105 Biological sciences
Abstract Human C5a is a plasma protein with potent chemoattractant and pro-inflammatory properties, and its overexpression correlates with severity of inflammatory diseases. C5a binds to its G protein-coupled receptor (C5aR) on polymorphonuclear leukocytes (PMNLs) through a high-affinity helical bundle and a low-affinity C terminus, the latter being solely responsible for receptor activation. Potent and selective C5a antagonists are predicted to be effective anti-inflammatory drugs, but no pharmacophore for small molecule antagonists has yet been developed, and it would significantly aid drug design. We have hypothesized that a turn conformation is important for activity of the C terminus of C5a and herein report small cyclic peptides that are stable turn mimics with potent antagonism at C5aR on human PMNLs. A comparison of solution structures for the C terminus of C5a, small acyclic peptide ligands, and cyclic antagonists supports the importance of a turn for receptor binding. Competition between a cyclic antagonist and either C5a or an acyclic agonist for C5aR on PMNLs supports a common or overlapping binding site on the C5aR. Structure-activity relationships for 60 cyclic analogs were evaluated by competitive radioligand binding with C5a (affinity) and myeloperoxidase release (antagonist potency) from human PMNLs, with 20 compounds having high antagonist potencies (IC50, 20 nM(-1) muM). Computer modeling comparisons reveal that potent antagonists share a common cyclic backbone shape, with affinity-determining side chains of defined volume projecting from the cyclic scaffold. These results define a new pharmacophore for C5a antagonist development and advance our understanding of ligand recognition and receptor activation of this G protein-coupled receptor.
Keyword Decapeptide Agonists
Ischemia-reperfusion
C-terminus
In-vitro
Rat
Anaphylatoxin
Injury
Conformation
Inflammation
Inhibition
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 14:43:38 EST