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.
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Authors | Iris 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 |
Journal | The 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 |
PMID | 19023040
(Publication Type: Journal Article)
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Chemical References |
- Anti-Inflammatory Agents
- CGEN-855A
- Cytokines
- FPR2 protein, human
- Peptides
- Receptors, Formyl Peptide
- Receptors, Lipoxin
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Topics |
- Animals
- Anti-Inflammatory Agents
(pharmacology)
- CHO Cells
- Cricetinae
- Cricetulus
- Cytokines
(metabolism)
- 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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