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

Angela M. Finch, Shawn M. Vogen, Simon A. Sherman, Leonid Kirnarsky, Stephen M. Taylor, Sam D. Sanderson

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

A conformationally biased decapeptide agonist of human C5a (C5a65- 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 β-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, C5a12-20-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.

Original languageEnglish (US)
Pages (from-to)877-884
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number6
DOIs
StatePublished - Mar 14 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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