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A novel peptide agonist of formyl-peptide receptor-like 1 (ALX) displays anti-inflammatory and cardioprotective effects.

Abstract
Activation of the formyl-peptide receptor-like (FPRL) 1 pathway has recently gained high recognition for its significance in therapy of inflammatory diseases. Agonism at FPRL1 affords a beneficial effect in animal models of acute inflammatory conditions, as well as in chronic inflammatory diseases. TIPMFVPESTSKLQKFTSWFM-amide (CGEN-855A) is a novel 21-amino acid peptide agonist for FPRL1 and also activates FPRL2. CGEN-855A was discovered using a computational platform designed to predict novel G protein-coupled receptor peptide agonists cleaved from secreted proteins by convertase proteolysis. In vivo, CGEN-855A displays anti-inflammatory activity manifested as 50% inhibition of polymorphonuclear neutrophil (PMN) recruitment to inflamed air pouch and provides protection against ischemia-reperfusion-mediated injury to the myocardium in both murine and rat models (36 and 25% reduction in infarct size, respectively). Both these activities are accompanied by inhibition of PMN recruitment to the injured organ. The secretion of inflammatory cytokines, including interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha, was not affected upon incubation of human peripheral blood mononuclear cells with CGEN-855A, whereas IL-8 secretion was elevated up to 2-fold upon treatment with the highest CGEN-855A dose only. Collectively, these new data support a potential role for CGEN-855A in the treatment of reperfusion-mediated injury and in other acute and chronic inflammatory conditions.
AuthorsIris Hecht, Jiang Rong, André L F Sampaio, Chen Hermesh, Caleb Rutledge, Ronen Shemesh, Amir Toporik, Merav Beiman, Liat Dassa, Hagit Niv, Gady Cojocaru, Arie Zauberman, Galit Rotman, Mauro Perretti, Jakob Vinten-Johansen, Yossi Cohen
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 2 Pg. 426-34 (Feb 2009) ISSN: 1521-0103 [Electronic] United States
PMID19023040 (Publication Type: Journal Article)
Chemical References
  • Anti-Inflammatory Agents
  • CGEN-855A
  • Cytokines
  • FPR2 protein, human
  • Peptides
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
Topics
  • Animals
  • Anti-Inflammatory Agents (pharmacology)
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cytokines (secretion)
  • Disease Models, Animal
  • Humans
  • Inflammation (prevention & control)
  • Leukocytes, Mononuclear (drug effects, metabolism)
  • Male
  • Mice
  • Myocardial Infarction (pathology, prevention & control)
  • Peptides (pharmacology, therapeutic use)
  • Rats
  • Receptors, Formyl Peptide (agonists)
  • Receptors, Lipoxin (agonists)

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