Received for publication September 16, 2008.
Revised November 19, 2008.
Accepted for publication November 19, 2008.

A novel peptide agonist of FPRL1 (ALX) displays anti-inflammatory and cardioprotective effects

Abstract

Activation of the Formyl-peptide receptor-like1 (FPRL1) 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. 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 GPCR peptide agonists cleaved from secreted proteins by convertase proteolysis. In vivo, CGEN-855A displays anti-inflammatory activity manifested as 50% inhibition of 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 IL-6, IL-1 and TNF was not affected upon incubation of human peripheral blood mononuclear cells (PBMCs) with CGEN-855A, while IL-8 secretion was elevated up to 2 fold upon treatment with 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.

Key words: Formyl- peptide receptor, cardioprotection, inflammation, ischemia-reperfusion, polymorphonuclear neutrophils, resolution of inflammation