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.
Department of Physiology and Pharmacology, University of Queensland, St. Lucia, QLD, Brisbane, QLD 4072, Australia.
S M
SM
Taylor
S A
SA
Sherman
L
L
Kirnarsky
S D
SD
Sanderson
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