Symmetrically substituted dichlorophenes inhibit N -acyl-phosphatidylethanolamine phospholipase D.

Autor: Aggarwal G; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232., Zarrow JE; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232., Mashhadi Z; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232., Flynn CR; Division of Surgery, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232., Vinson P; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232., Weaver CD; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232., Davies SS; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232. Electronic address: sean.davies@vanderbilt.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2020 May 22; Vol. 295 (21), pp. 7289-7300. Date of Electronic Publication: 2020 Apr 13.
DOI: 10.1074/jbc.RA120.013362
Abstrakt: N -Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of N -acyl-ethanolamides. Reduced NAPE-PLD expression and activity may contribute to obesity and inflammation, but a lack of effective NAPE-PLD inhibitors has been a major obstacle to elucidating the role of NAPE-PLD and N -acyl-ethanolamide biosynthesis in these processes. The endogenous bile acid lithocholic acid (LCA) inhibits NAPE-PLD activity (with an IC 50 of 68 μm), but LCA is also a highly potent ligand for TGR5 (EC 50 0.52 μm). Recently, the first selective small-molecule inhibitor of NAPE-PLD, ARN19874, has been reported (having an IC 50 of 34 μm). To identify more potent inhibitors of NAPE-PLD, here we used a quenched fluorescent NAPE analog, PED-A1, as a substrate for recombinant mouse Nape-pld to screen a panel of bile acids and a library of experimental compounds (the Spectrum Collection). Muricholic acids and several other bile acids inhibited Nape-pld with potency similar to that of LCA. We identified 14 potent Nape-pld inhibitors in the Spectrum Collection, with the two most potent (IC 50 = ∼2 μm) being symmetrically substituted dichlorophenes, i.e. hexachlorophene and bithionol. Structure-activity relationship assays using additional substituted dichlorophenes identified key moieties needed for Nape-pld inhibition. Both hexachlorophene and bithionol exhibited significant selectivity for Nape-pld compared with nontarget lipase activities such as Streptomyces chromofuscus PLD or serum lipase. Both also effectively inhibited NAPE-PLD activity in cultured HEK293 cells. We conclude that symmetrically substituted dichlorophenes potently inhibit NAPE-PLD in cultured cells and have significant selectivity for NAPE-PLD versus other tissue-associated lipases.
(© 2020 Aggarwal et al.)
Databáze: MEDLINE
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