Search

Areas Covered: This review article summarizes the most important synthetic PLA 2 inhibitors developed to target each one of the four major types of human PLA 2 (cytosolic cPLA 2 , calcium-independent iPLA 2 , secreted sPLA 2 , and lipoprotein-associated Lp-PLA 2 ), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA 2 in the pathobiology of COVID-19 are also discussed., Expert Opinion: Although a number of PLA 2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA 2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA 2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA 2 , varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA 2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal.

Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated α-synuclein in the affected neurons. The aggregation properties of α-synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, α-synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of α-helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A 2 (PLA 2 ). To investigate the impact of PLA 2 activity on α-synuclein aggregation, we have applied selective PLA 2 inhibitors to a SH-SY5Y cellular model where the expression of human wild-type α-synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA 2 resulted in a dramatic decrease of intracellular oligomeric and monomeric α-synuclein significantly promoting cell survival. Our data suggest that alterations in the levels of free fatty acids, and especially AA and adrenic acid, promote the formation of α-synuclein conformers which are more susceptible to proteasomal degradation. This mechanism is active only in living cells and is generic since it does not depend on the absolute quantity of α-synuclein, the presence of disease-linked point mutations, the expression system or the type of cells. Our findings indicate that the α-synuclein-fatty acid interaction can be a critical determinant of the conformation and fate of α-synuclein in the cell interior and, as such, cPLA 2 inhibitors could serve to alleviate the intracellular, potentially pathological, α-synuclein burden., (© 2020 Federation of American Societies for Experimental Biology.)

2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A 2 (GIVA cPLA 2 ) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester inhibitors of GIVA cPLA 2 have been developed, their rapid degradation in human plasma limits their pharmaceutical utility. In an effort to address this problem, we designed and synthesized two new 2-oxoesters introducing a methyl group either on the α-carbon to the oxoester functionality or on the carbon carrying the ester oxygen. We studied the in vitro plasma stability of both derivatives and their in vitro inhibitory activity on GIVA cPLA 2 . Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA 2 , however to different degrees. The 2-oxoester containing a methyl group on the α-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency., Competing Interests: The authors have declared no conflict of interest.

Phospholipase A 2 (PLA 2 ) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA 2 inhibitors developed to target each one of the four major types of human PLA 2 (cytosolic cPLA 2 , calcium-independent iPLA 2, secreted sPLA 2, and lipoprotein-associated LpPLA 2 ). We discuss recent applications of inhibitors to understand the role of each PLA 2 type and their therapeutic potential. Potent and selective PLA 2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA 2 inhibitors are excellent tools to unveil the role that each PLA 2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA 2 inhibitors as new agents to treat inflammatory diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ca 2+ -independent phospholipase A 2 (GVIA iPLA 2 ) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA 2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA 2 inhibitors based on the β-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA 2 inhibitor ever reported ( X I (50) 0.0000021, IC 50 1 nM) and also one that is 22 000 times more active against GVIA iPLA 2 than GIVA cPLA 2 . It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.

Introduction: The regulation of the catalytic activity of the various phospholipase A 2 enzymes is of high importance because these enzymes are involved in various pathological conditions such as arthritis, cardiovascular diseases, neurological diseases, and cancer. Thus, a great effort has been devoted in developing synthetic inhibitors as new agents to treat inflammatory diseases. Some of them have reached clinical trials. Areas covered: This review article discusses the phospholipase A 2 inhibitors presented in patent literature from October 2012 to June 2016, their activities in vitro and in vivo as well as the results of clinical trials using synthetic PLA 2 inhibitors. Expert opinion: None of the inhibitors studied in clinical trials have reached the market yet. The failure of lipoprotein-associated PLA 2 inhibitor darapladib to reduce the risk of major coronary events suggests that this enzyme may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular diseases. These findings, together with the failure of secreted PLA 2 inhibitor varespladib for the treatment of cardiovascular disease, indicate that deeper knowledge on these enzymes is needed. Inhibitors of cytosolic PLA 2 are in clinical trials against psoriasis and atopic dermatitis.

Calcium-independent phospholipase A 2 (GVIA iPLA 2 ) has recently attracted interest as a medicinal target. The number of known GVIA iPLA 2 inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA 2 and their selectivity over the other major intracellular GIVA cPLA 2 and the secreted GV sPLA 2 . Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA 2 (X I (50) value of 0.007) and at the same time significant selectivity over GIVA cPLA 2 and GV sPLA 2 ., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-γ-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-α-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The development of inhibitors for phospholipase A2 (PLA2) is important in elucidating the enzymes implication in various biological pathways. PLA2 enzymes are an important pharmacological target implicated in various inflammatory diseases. Computational chemistry, organic synthesis, and in vitro assays were employed to develop potent and selective inhibitors for group VIA calcium-independent PLA2. A set of fluoroketone inhibitors was studied for their binding mode with two human cytosolic PLA2 enzymes: group IVA cPLA2 and group VIA iPLA2. New compounds were synthesized and assayed toward three major PLA2s. This study led to the development of four potent and selective thioether fluoroketone inhibitors as well as a thioether keto-1,2,4-oxadiazole inhibitor for GVIA iPLA2, which will serve as lead compounds for future development and studies. The keto-1,2,4-oxadiazole functionality with a thioether is a novel structure, and it will be used as a lead to develop inhibitors with higher potency and selectivity toward GVIA iPLA2.

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.

Group VIA calcium-independent phospholipase A2 (GVIA iPLA2) has recently emerged as an important pharmaceutical target. Selective and potent GVIA iPLA2 inhibitors can be used to study its role in various neurological disorders. In the current work, we explore the significance of the introduction of a substituent in previously reported potent GVIA iPLA2 inhibitors. 1,1,1,2,2-Pentafluoro-7-(4-methoxyphenyl)heptan-3-one (GK187) is the most potent and selective GVIA iPLA2 inhibitor ever reported with a XI(50) value of 0.0001, and with no significant inhibition against GIVA cPLA2 or GV sPLA2. We also compare the inhibition of two difluoromethyl ketones on GVIA iPLA2, GIVA cPLA2, and GV sPLA2., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The phospholipase A(2) (PLA(2)) superfamily consists of different groups of enzymes which are characterized by their ability to catalyze the hydrolysis of the sn-2 ester bond in a variety of phospholipid molecules. The products of PLA(2s) activity play divergent roles in a variety of physiological processes. There are four main types of PLA(2s): the secreted PLA(2s) (sPLA(2s)), the cytosolic PLA(2s) (cPLA(2s)), the calcium-independent PLA(2s) (iPLA(2)) and the lipoprotein-associated PLA(2s) (LpPLA(2s)). Various potent and selective PLA2 inhibitors have been reported up to date and have provided outstanding support in understanding the mechanism of action and elucidating the function of these enzymes. The current review focuses on the implementation of rational design through computer-aided drug design (CADD) on the discovery and development of new PLA(2) inhibitors.

Automated docking allowing a "protein-based" alignment was performed on a set of indole inhibitors of the GIIA secreted phospholipase A(2) (GIIA sPLA(2)). A correlation between the binding scores and the experimental inhibitory activity was observed (r(2) = 0.666, N = 34). All the indole inhibitors were docked in the active site of the GIIA sPLA(2) enzyme, and the best score docking pose of each inhibitor was used for the "protein-based" alignment of the compounds. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was then established using the comparative molecular field analysis (CoMFA) method. The set of 34 indole inhibitors was divided into two subsets: the training set, composed of 26 compounds, and the test set, consisting of eight compounds. The robustness and the predictive ability of the generated CoMFA model were examined by using the test set. A good correlation (r(2) = 0.997) between predicted and experimental inhibitory activity data allows the validation of the CoMFA model. Finally, the generated CoMFA model was used for the design and evaluation of new compounds. The new designed compounds exert improved predicted inhibitory activity and may be a target for the synthesis of new GIIA sPLA(2) indole inhibitors.

Docking calculations that allow the estimation of the binding energy of small ligands in the GIIA sPLA(2) active site were used in a structure-based design protocol. Four GIIA sPLA(2) inhibitors co-crystallised with the enzyme, were used for examining the enzyme active site and for testing the FlexX in SYBYL 6.8 molecular docking program to reproduce the crystallographic experimental data. The FPL67047XX inhibitor was chosen as a prototype structure for applying free energy perturbation (FEP) studies. Structural modifications of the initial structure of the FPL67047XX inhibitor (IC(50) 0.013 microM) were performed in an effort to optimise the interactions in the GIIA sPLA(2) active site. The structural modifications were based on: (1) the exploration of absolute configuration (i.e. comparison of the binding score of (R)- and (S)-enantiomers); (2) bioisosterism (i.e. replacement of the carboxylate group with the bioisosteric sulphonate and phosphonate groups); (3) insertion of substituents that fit better in the active site. The generated new structures exhibited higher binding energy. Such structures may spark off the interest of medicinal chemists for synthesizing potentially more active GIIA sPLA(2) inhibitors.

Importance of the Field: The various phospholipase A(2) (PLA(2)) types have been implicated in diverse kinds of lipid signaling and inflammatory diseases. Rheumatoid arthritis, lung inflammation, neurological disorders, such as multiple sclerosis, cardiovascular diseases, including atherosclerosis, and cancer are included among the diseases where PLA(2) enzymes are involved. Thus, there is a great interest in developing potent and selective PLA(2) inhibitors and some of them have entered clinical trials., Areas Covered in This Review: This review article discusses the role of each PLA(2) class in inflammatory diseases and the advances in the development of inhibitors presented in patent literature from January 2004 to May 2009., What the Reader Will Gain: PLA(2)s cluster in four main types: secreted sPLA(2), cytosolic cPLA(2), Ca(2+)-independent iPLA(2) and lipoprotein-associated LpPLA(2). Each of those types has been implicated in diverse kinds of inflammatory diseases. Readers will rapidly gain an overview of the various PLA(2) inhibitors reported in the patent literature in the past 5 years. Furthermore, the readers will learn the difficulties related to the development of PLA(2) inhibitors as new drugs and also the different companies and research groups that are the main players in the field., Take Home Message: Although the role of each PLA(2) is not yet distinct in different diseases, the development and future use of different PLA(2) inhibitors to treat human disease seems very promising.

A variety of 2-oxoamides and related amides based on natural and non-natural amino acids were synthesized. Their activity on two human intracellular phospholipases (GIVA cPLA(2) and GVIA iPLA(2)) and one human secretory phospholipase (GV sPLA(2)) was evaluated. We show that an amide based on (R)-gamma-norleucine is a highly selective inhibitor of GV sPLA(2).

A variety of lipophilic 2-oxoamides based on gamma-aminobutyric and delta-aminovaleric analogues were synthesized. 2-oxoamides containing a tetrazole, a thioethyl or a thioacetyl group are weak inhibitors of GIVA cPLA(2), while derivatives containing a methyl tetrazole, a diethyl phosphonate or a thioethyl group are weak inhibitors of GV sPLA(2)., (Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.)