Development of response-selective agonists of human C5a anaphylatoxin: Conformational, biological, and therapeutic considerations

Stephen M. Taylor, Simon A. Sherman, Leonid Kirnarsky, Sam D. Sanderson

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Numerous studies on the relationship between the structure and function of peptide agonists derived from the biologically active, C-terminal region of human C5a anaphylatoxin have been reported over the past decade. These studies have been performed with the objective of parlaying this structure-function information into the design of peptide/peptidomimetic modulators of C5a receptor (C5aR)-mediated function. In this review, we describe a rational approach for the development of conformationally biased, decapeptide agonists of C5a and described how these stabilized and specific conformational features relate to the expression of specific C5a-like activities in vitro and in vivo. The therapeutic potential of such response-selective C5a agonists is discussed and underscored by the results of one such response-selective C5a agonist that was used in vivo as an effective molecular adjuvant capable of generating antigen-specific humoral and cellular immune responses. Finally, we describe the synthesis of a new generation of highly response-selective, conformationally biased C5a agonist and discuss the in vitro and in vivo biologic results that so indicate this biologic selectivity.

Original languageEnglish (US)
Pages (from-to)675-684
Number of pages10
JournalCurrent medicinal chemistry
Volume8
Issue number6
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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