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-1β, and tumor necrosis factor-α, 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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.145821.
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ABBREVIATIONS: I/R, ischemia-reperfusion; FPRL, formyl-peptide receptor-like; GPCR, G protein-coupled receptor; LXA4, lipoxin A4; PMN, polymorphonuclear neutrophil; FPR, formyl-peptide receptor; CGEN-855A, TIPMFVPESTSKLQKFTSWFM-amide; CHO, Chinese hamster ovary; FCS, fetal calf serum; CI, cell index; BSA, bovine serum albumin; PBS, phosphate-buffered saline; LCA, left coronary artery; AAR, area at risk; LV, left ventricle/ventricular; ELISA, enzyme-linked immunosorbent assay; PBMC, peripheral blood mononuclear cell; IL, interleukin; TNF, tumor necrosis factor; Ac2-26, acetyl-AMVSEFLKQAWFIENEEQEYVVQTVK.
- Received September 14, 2008.
- Accepted November 19, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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