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-1␤, and tumor necrosis factor-␣, 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 reperfusionmediated injury and in other acute and chronic inflammatory conditions.

The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease

“…The subcutaneous administration of annexin-A1 N-terminal derived peptide Ac2-26 has been shown to confer protection against ischemia-reperfusion injury by reducing myeloperoxidase activity and IL-1β levels in the infarcted heart, as well as down-regulate monocyte accumulation and inhibit phagocytic activity of macrophages in different rodent experimental models (Getting et al, 1997; La et al, 2001). Another annexin-A1 mimetic is CGEN-855A, a 21 amino acid peptide displays anti-inflammatory effects by inhibition of polymorphonuclear neutrophils recruitment and also provides protection against ischemia-reperfusion-mediated injury to the myocardium after being injected intravenously in mice (Hecht et al, 2009). …”

Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2) Agonists

“…TIPMFVPESTSKLQKFTSWFM-amide (CGEN-855A) is a 21 amino acids peptide isolated by a computational platform designed to predict novel GPCR agonists cleaved from secreted proteins by convertase proteolysis [140]. It triggers calcium mobilization and an increase of the cell impedance index in cells expressing either FPR2 or FPR3, but does not affect monocyte secretion of cytokines.…”

“…It triggers calcium mobilization and an increase of the cell impedance index in cells expressing either FPR2 or FPR3, but does not affect monocyte secretion of cytokines. In vivo , CGEN-855A displays anti-inflammatory activity and protection against ischemia-reperfusion-mediated injury to the myocardium, which is accompanied by inhibition of PMN recruitment to the injured organ [140]. …”

Annexin A1 and the regulation of innate and adaptive immunity

“…For example, Amgen have developed a program to identify small chemical entities that are specific for FPR2/ALXR (Perretti and Dalli, 2009). In addition, novel computer modeling approaches are now being used to identify ligands that are specific for members of the FPR family, in several cases for FPR2/ALXR (Shemesh et al, 2008; Hecht et al, 2009). The ultimate aim of this work is to identify a low molecular weight compound with the capacity to interact with FPR2/ALXR to mediate a comparable profile of anti-inflammatory effects to that of AnxA1…”