Decapeptide Agonists of Human C5a: The Relationship between Conformation and Spasmogenic and Platelet Aggregatory Activities

Abstract

A series of decapeptide analogues corresponding to the C-terminal region of human C5a anaphylatoxin (C5a65-74) was synthesized with residue substitutions to restrict conformational flexibility in the C-terminus. These conformationally constrained peptides behaved as agonists of C5a in spasmogenic assays (smooth muscle contraction in human fetal artery, guinea pig ileum, and guinea pig lung parenchyma) as well as guinea pig platelet aggregation. There were significant correlations in the potencies of these peptides between the various assays. A structure-function analysis led to the identification of a preferred backbone conformation that correlated with the expression of these biological responses. These backbone structural motifs were consistent with a helix-like conformation for residues 65-69, an elongated structure for residues 70-71, and a beta-turn of either type II or type V for residues (71)72-74. The most potent of these agonists expressed almost 5% of the potency of natural C5a.

Induction of an Antigen-Specific CTL Response by a Conformationally Biased Agonist of Human C5a Anaphylatoxin as a Molecular Adjuvant

“…All peptides were characterized by amino acid compositional analysis and mass spectrometry. The details of these methods of synthesis, purification, and characterization have been described previously (6).…”

The Conserved TFLK Motif of Mammary-Associated Serum Amyloid A3 Is Responsible for Up-regulation of Intestinal MUC3 Mucin Expression In Vitro

“…Peptides were purified by analytical and preparative HPLC columns packed with C 18 -bonded silica gel and were characterized by amino acid compositional analysis and mass spectrometry. The details of these methods have been previously reported (20).…”

Peptídeos de conformação restrita relacionados ao sítio 2 do fator de crescimento de fibroblastos ácido humano (hFGF-1): estudo sobre estrutura e atividade

“…2 contribuido amplamente para a compreensão dos mecanismos de ação de inúmeros peptídeos biologicamente ativos, para a determinação de suas conformações biologicamente ativas e também para a descoberta de análogos mais potentes (Chamberlin et al, 1995; Wells,1996;Sanderson et al, 1994).…”

“…Como já foi citado, os peptídeos sintéticos tem tido grande destaque na literatura em função de sua ampla aplicabilidade no desenvolvimento de pesquisa em bioquímica (Chorev et al, 1991;Fauchère & Thurieau, 1992;Sanderson et al, 1994;Gutte & Klauser, 1995; Muir et al., 1997;Tam & Spetzler, 1997;Burke & Zangh, 1998). Como exemplo, os mesmos podem auxiliar na busca de agonistas ou inibidores peptídicos efetivos de proteínas de grande importância biológica Wrighton et al, 1996).…”

“…Estas questões puderam ser investigadas graças aos avanços crescentes da química de peptídeos que possibilitaram a obtenção de peptídeos de conformação restrita (Struthers et al, 1996). Estes compostos tem contribuido amplamente para a compreensão dos mecanismos de ação de inúmeros peptídeos biologicamente ativos, para a determinação de suas conformações biologicamente ativas e também para a descoberta de análogos mais potentes (Chamberlin et al, 1995;Wells,1996;Sanderson et al, 1994). …”