Differential activities of decapeptide agonists of human C5a: The conformational effects of backbone N-methylation

Shawn M. Vogen, Natalii J. Paczkowski, Leonid Kirnarsky, Anna Short, Jacqueline B. Whitmore, Simon A. Sherman, Stephen M. Taylor, Sam D. Sanderson

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Analogues of the potent, conformationally biased, decapeptide agonist of human C5a anaphylatoxin, C5a65-74Y65,F67,P69,P71,D-Ala73 (YSFKPMPLaR, peptide 54), were synthesized with methyl groups occupying specific amide nitrogen atoms along the peptide backbone. This N-methylation induced crucial extended backbone conformations in a manner similar to the two Pro residues, but without eliminating the contributions made by the side-chain of the residue for which Pro was substituted. The presence of backbone N-methyl groups on peptide 54 analogues had pronounced detrimental effects on the ability to bind and activate C5aRs expressed on human PMNs, but not on the ability to contract smooth muscle of human umbilical artery. Several N-methylated analogues of peptide 54 (peptides 56, 67, 124, 125, and 137) were significantly more selective for smooth muscle contraction, which is mediated by tissue resident macrophages, than for enzyme release from PMNs. Indeed, peptide 67, YSFKDMP(MeL)aR was almost 3000-fold more selective for smooth muscle contraction than for PMN enzyme release. Consistent with these differential activities was the observation that peptide 67 expressed a significantly greater binding affinity to C5aRs expressed on rat macrophages than on rat PMNs. This differential activity was also observed in vivo in the rat where peptide 67 induced a hypotensive response similar to peptide 54 and rhuC5a, but without accompanying neutropenia.

Original languageEnglish (US)
Pages (from-to)2151-2162
Number of pages12
JournalInternational Immunopharmacology
Issue number12
StatePublished - 2001


  • N-methylation
  • Response-selective C5a agonists

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology


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