Development of response-selective agonists of human C5a anaphylatoxin: conformational, biological, and therapeutic considerations.
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.
Taylor
S M
SM
Department of Physiology and Pharmacology, University of Queensland, St. Lucia, QLD, Brisbane, QLD 4072, Australia.
Sherman
S A
SA
Kirnarsky
L
L
Sanderson
S D
SD
D000818:Animals; D015936:Complement C5a / Q000819:agonists* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D011487:Protein Conformation; D011951:Receptors, Complement / Q000187:drug effects; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010446:Peptide Fragments; D011951:Receptors, Complement; C105322:complement C5a, (65-74), Tyr(65)-Phe(67)-Pro(69,71)-Ala(73)-; D015936:Complement C5a