A novel peptide agonist of formyl-peptide receptor-like 1 (ALX) displays anti-inflammatory and cardioprotective effects.
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.
Hecht
Iris
I
Compugen Ltd., 72 Pinchas Rosen St., Tel Aviv, Israel 69512. iris.hecht@cgen.com
Rong
Jiang
J
Sampaio
André L F
AL
Hermesh
Chen
C
Rutledge
Caleb
C
Shemesh
Ronen
R
Toporik
Amir
A
Beiman
Merav
M
Dassa
Liat
L
Niv
Hagit
H
Cojocaru
Gady
G
Zauberman
Arie
A
Rotman
Galit
G
Perretti
Mauro
M
Vinten-Johansen
Jakob
J
Cohen
Yossi
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D044067:Receptors, Lipoxin / Q000819:agonists*
D000893:Anti-Inflammatory Agents; C535230:CGEN-855A; D016207:Cytokines; C105101:FPR2 protein, human; D010455:Peptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin