Biologically active conformer of the effector region of human C5a and modulatory effects of N-terminal receptor binding determinants on activity

Finch, AM, Vogen, SM, Sherman, SA, Kirnarsky, L, Taylor, SM and Sanderson, SD (1997) Biologically active conformer of the effector region of human C5a and modulatory effects of N-terminal receptor binding determinants on activity. Journal of Medicinal Chemistry, 40 6: 877-884.


Author Finch, AM
Vogen, SM
Sherman, SA
Kirnarsky, L
Taylor, SM
Sanderson, SD
Title Biologically active conformer of the effector region of human C5a and modulatory effects of N-terminal receptor binding determinants on activity
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 1997
Sub-type Article (original research)
DOI 10.1021/jm960727r
Volume 40
Issue 6
Start page 877
End page 884
Total pages 8
Language eng
Abstract A conformationally biased decapeptide agonist of human C5a (C5a(65-74)Y65,F67,P69,P71,D-Ala73 or YSFKPMPLaR) was used as a functional probe of the C5a receptor (C5aR) in order to understand the conformational features in the C-terminal effector region of C5a that are important for C5aR binding and signal transduction. YSFKPMPLaR was a potent, full agonist of C5a, but at higher concentrations had a superefficacious effect compared to the natural factor. The maximal efficacy of this analogue was 216 +/- 56% that of C5a in stimulating the release of beta-glucuronidase from human neutrophils. C5aR activation and binding curves both occurred in the same concentration range with YSFKPMPLaR, characteristics not observed with natural C5a or more conformationally flexible C-terminal agonists. YSFKPMPLaR was then used as a C-terminal effector template onto which was synthesized various C5aR binding determinants from the N-terminal core domain of the natural factor. In general, the presence of N-terminal binding determinants had little effect on either potency or binding affinity when the C-terminal effector region was presented to the C5aR in this biologically active conformation. However, one peptide, C5a(12-20)-Ahx-YSFKPMPLaR, expressed a 100-fold increase in affinity for the neutrophil C5aR and a 6-fold increase in potency relative to YSFKPMPLaR. These analyses showed that the peptides used in this study have up to 25% of the potency of C5a in human fetal artery and up to 5% of the activity of C5a in the PMN enzyme release assay.
Keyword Chemistry, Medicinal
Human Anaphylatoxin C5a
Decapeptide Agonists
Identification
Site
Interleukin-1
Stimulation
Expression
Induction
Monocytes
Release
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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Created: Mon, 13 Aug 2007, 16:42:16 EST