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Review
. 2019 Jun;1864(6):941-956.
doi: 10.1016/j.bbalip.2018.08.009. Epub 2018 Aug 23.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

Aikaterini Nikolaou  1 , Maroula G Kokotou  1 , Sofia Vasilakaki  1 , George Kokotos  2
Affiliations
Review

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

Aikaterini Nikolaou et al. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Jun.

Erratum in

Abstract

Phospholipase A2 (PLA2) 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 PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated LpPLA2). We discuss recent applications of inhibitors to understand the role of each PLA2 type and their therapeutic potential. Potent and selective PLA2 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, PLA2 inhibitors are excellent tools to unveil the role that each PLA2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA2 inhibitors as new agents to treat inflammatory diseases.

Keywords: Clinical trials; Inflammation; Inhibitors; Phospholipase A(2).

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Figures

Fig. 1
Fig. 1
Structures of GIVA cPLA2 inhibitors.
Fig. 2
Fig. 2
Structure of GVIA iPLA2 monomer.
Fig. 3
Fig. 3
Structures of GVIA iPLA2 inhibitors.
Fig. 4
Fig. 4
Structures of sPLA2 inhibitors.
Fig. 5
Fig. 5
Structures of LpPLA2 inhibitors.
Fig. 6
Fig. 6
Binding mode of PAPC substrate in the active site of GIVA cPLA2.
Fig. 7
Fig. 7
Left: Binding mode of inhibitor GK187 in GVIA iPLA2. Right: Binding mode of inhibitor FKGK18 in GVIA iPLA2.
Fig. 8
Fig. 8
Interactions of thioether 18 with the residues of GVIA iPLA2.
Fig. 9
Fig. 9
Binding mode of inhibitor GK452 in the active site of GIVA cPLA2.
Fig. 10
Fig. 10
Conformational arrangement of GK241 in the binding pocket of GIIA sPLA2.
See this image and copyright information in PMC

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