Decapeptide Agonists of Human C5a: The Relationship between Conformation and Neutrophil Response

Sam D. Sanderson, Leonid Kirnarsky, Simon Sherman, Shawn M. Vogen, Om Prakash, Julia A. Ember, Angela M. Finch, Stepen M. Taylor

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

A series of decapeptide analogues corresponding to the C-terminal region of the human C5a anaphylatoxin (C5a65-74) was synthesized with residue substitutions to restrict conformational flexibility in the C-terminal region (residues 71-74). These analogues behaved as full agonists of natural C5a in their ability to induce shape change (polarization) and the release of enzyme (β-glucuronidase) from human neutrophils (PMNs). There was a significant pharmacological correlation between the polarization and enzyme-release assays, suggesting similarities in PMN responsiveness toward these constrained peptides. Good correlations were also observed between these two PMN responses and spasmogenic activity (smooth muscle contraction of human fetal artery). A structure-function analysis for PMN polarization and enzyme release led to the identification of the following preferred backbone conformations: a twisted, helixlike conformation for residues 65-69, an extended conformation for residues 70-71, and a β-turn of type V for residues (71)72-74. The existence of a C-terminal, type V β-tum is supported by the NOE (nuclear Overhauser effect) results of two peptides from this series. These conformational features are reminiscent of those that were shown to correlate with the expression of spasmogenic and platelet aggregatory activities in an earlier investigation (Sanderson, S. D.; et al. J. Med. Chem. 1994, 37, 3171). These results suggest that PMNs and the cells responsible for smooth muscle contraction possess C5a receptors that respond to similar topochemical features presented by the agonist peptide ligand.

Original languageEnglish (US)
Pages (from-to)3669-3675
Number of pages7
JournalJournal of Medicinal Chemistry
Volume38
Issue number18
DOIs
StatePublished - Sep 1 1995

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Neutrophils
Muscle Contraction
Peptides
Anaphylatoxin C5a Receptor
Anaphylatoxins
Glucuronidase
Enzyme Assays
Enzymes
Smooth Muscle
Blood Platelets
Arteries
Pharmacology
Ligands

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Sanderson, S. D., Kirnarsky, L., Sherman, S., Vogen, S. M., Prakash, O., Ember, J. A., ... Taylor, S. M. (1995). Decapeptide Agonists of Human C5a: The Relationship between Conformation and Neutrophil Response. Journal of Medicinal Chemistry, 38(18), 3669-3675. https://doi.org/10.1021/jm00018a028

Decapeptide Agonists of Human C5a : The Relationship between Conformation and Neutrophil Response. / Sanderson, Sam D.; Kirnarsky, Leonid; Sherman, Simon; Vogen, Shawn M.; Prakash, Om; Ember, Julia A.; Finch, Angela M.; Taylor, Stepen M.

In: Journal of Medicinal Chemistry, Vol. 38, No. 18, 01.09.1995, p. 3669-3675.

Research output: Contribution to journalArticle

Sanderson, SD, Kirnarsky, L, Sherman, S, Vogen, SM, Prakash, O, Ember, JA, Finch, AM & Taylor, SM 1995, 'Decapeptide Agonists of Human C5a: The Relationship between Conformation and Neutrophil Response', Journal of Medicinal Chemistry, vol. 38, no. 18, pp. 3669-3675. https://doi.org/10.1021/jm00018a028
Sanderson, Sam D. ; Kirnarsky, Leonid ; Sherman, Simon ; Vogen, Shawn M. ; Prakash, Om ; Ember, Julia A. ; Finch, Angela M. ; Taylor, Stepen M. / Decapeptide Agonists of Human C5a : The Relationship between Conformation and Neutrophil Response. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 18. pp. 3669-3675.
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