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Editorial [Phospholipases: A Target for "New Leads" in the Modulation of Inflammation Processes Guest Editor: D. Hadjipavlou-Litina]

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Phospholipase A2 constitutes a large and diverse family of enzymes, which catalyze the hydrolysis of membrane glycerophospholipids at the sn-2 position to release fatty acids and lysophospholipids. When the fatty acid is the arachidonic acid, a complementary metabolism leads to pro-inflammatory mediators such as prostaglandins, leukotrienes, thromboxanes and platelet activating factors. Thus, modulating pro-inflammatory lipid mediator production by inhibiting PLA2 activity remains a potential target for the development of new drugs for the treatment of inflammatory diseases.

Many different PLA2 are present in the mammalian organism. They can be divided in PLA2s utilizing a catalytic histidine and in PLA2s having a serine in the active site. Thus, a problem associated with the in vitro search for PLA2 inhibitors is the selection of the appropriate enzyme.

All the above facts prompted us to deal with phospholipases in a thematic issue, as a biomolecule target for "new leads" in the modulation of inflammation processes.

In their contribution Lehr et al., describe the different assays applied for the evaluation of cPLA2 inhibitors in vitro and in vivo. Furthermore, they present the structures and inhibition data of known cPLA2a inhibitors and discuss the problems associated with the development of a clinical active drug candidate. Since it is difficult to compare the in vitro inhibition data of enzyme inhibitors as far as they are monitored with different assays, the authors also present such data for some interesting cPLA2a inhibitors determined with the same assay.

Inflammatory mediators contribute significantly to the induction and progression of cardiovascular diseases such as atherosclerosis and acute myocardial infarction (AMI). A mediator that has been shown to play a crucial role in both cardiovascular events is group-II secretory phospholipase A2 (sPLA2-II), as this mediator has been suggested to modulate atherosclerotic plaque formation, for example by increasing the accumulation of intracellular lipids in macrophages and stimulating the formation of foam cells. Furthermore, increased levels of sPLA2-II in the blood form a risk marker for the development of complications of coronary artery disease. In line with this, Krijnen et al., have recently found that extracellular sPLA2-II is more abundantly present in the extracellular matrix of atherosclerotic culprit lesions of coronary arteries in patients who developed AMI than in those of patients with stable or unstable angina pectoris. Another important feature of sPLA2-II is its abilty to bind to and hydrolyze membrane phospholipids. Notably, sPLA2-II cannot bind to the tightly packed hydrophobic phospholipids in the outer leaflet of a normal membrane, but only to the disarranged or flip-flopped membranes of damaged cells, as is the case in ischemic jeopardized cardiomyocytes. Interestingly, Krijnen et al., have recently observed that sPLA2-II cannot only bind to reversible damaged cardiomyocytes but also induces these cells to die, partly by potentiating binding of Creactive protein and thus inducing an inflammatory response in the ischemically challenged heart.

From this point of view, Krijnen and co-investigators discuss in their review the pros and cons of therapy with inhibitors of sPLA2-II to prevent complications of the process of atherosclerosis, and/or to limit the amount of cell death of cardiomyocytes subsequent to AMI.

Hnps-PLA2 has been crystallized with different ligands and several classes of inhibitors are known, but the optimization of their therapeutic properties requires: (i) a better understanding of the inhibitor-protein interaction mechanism, and (ii) finding a strategy to predict the activity of new molecules. Approaches related to computational chemistry may help to resolve these two problems and these are included in the review of Chretien's et al.

An automated docking study was performed on a series of 188 competitive hnps-PLA2 inhibitors. The docking data were then used to establish 3D QSAR models by combining Comparative Molecular Field Analysis (CoMFA) and PLS modeling. The robustness and prediction power of the best model were assessed with the help of cross-validation and test set procedures that delivered excellent scores. The combination of the two models generated on hnps-PLA2 and hp-PLA2 offered a global predictive tool able to select new strong anti-inflammatory drugs with negligible side effects, at least at pancreatic level. In the last review, Kokotos et al., summarize the chemical classes of reversible and irreversible inhibitors of both GIVA PLA2 and GVIA PLA2. Structures, synthesis and inhibition data for both enzymes are presented.
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Document Type: Research Article

Affiliations: Department of Pharmaceutical Chemistry School of Pharmacy, Aristotelian University of Thessaloniki Thessaloniki, 54124 Greece.

Publication date: 2006-05-01

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  • Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new Anti-Inflammatory & Anti-Allergy Agents.

    Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in Anti-Inflammatory & Anti-Allergy Medicinal Chemistry.

    Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in Anti-Inflammatory & Anti-Allergy Agents drug discovery.
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