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Symmetrically Substituted Dichlorophenes Inhibit N-Acyl-Phosphatidylethanolamine Phospholipase D

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Symmetrically Substituted Dichlorophenes Inhibit N-Acyl-Phosphatidylethanolamine Phospholipase D bioRxiv preprint doi: https://doi.org/10.1101/2020.03.05.979567; this version posted March 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Symmetrically substituted dichlorophenes inhibit N-acyl-phosphatidylethanolamine phospholipase D Geetika Aggarwal1, Jonah E. Zarrow1, Zahra Mashhadi1, C. Robb Flynn2, Paige Vinson1,3, C. David Weaver1,4, and *Sean S. Davies1,4,5. 1Department of Pharmacology, 3Vanderbilt Center for Neuroscience Drug Discovery, 4Vanderbilt Institute of Chemical Biology, 5Division of Clinical Pharmacology, Vanderbilt University, and 2Division of Surgery, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Running title: Novel NAPE-PLD inhibitors Corresponding Author: Sean S. Davies, 556B RRB, Department of Pharmacology, Division of Clinical Pharmacology, Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN37232-6602, USA. Phone: 615.322.5049; E-mail: [email protected]. Key words: N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD); N-acyl-ethanolamides (NAE); Bile acid; Dichlorophene. Abstract inhibited NAPE-PLD activity in cultured HEK293 cells. N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in Introduction the biosynthesis of N-acyl-ethanolamides (NAEs). Reduced NAPE-PLD expression and activity may N-acyl-ethanolamide (NAE) biosynthesis and contribute to obesity and inflammation, but a major signaling appear to play important roles in regulating obstacle to elucidating the role of NAPE-PLD and energy balance, inflammation, stress responses, and NAE biosynthesis in various physiological processes addiction (1-6). Saturated and monounsaturated has been the lack of effective NAPE-PLD inhibitors. NAEs like N-palmitoyl-ethanolamide (C16:0NAE) The endogenous bile acid lithocholic acid (LCA) and N-oleoyl-ethanolamide (C18:1NAE) act on inhibits NAPE-PLD activity (IC50 68 μM) but LCA is GPR55 and GPR119, respectively, as well as on also a highly potent ligand for TGR5 (EC50 0.52 μM). PPARα (7-13). Pharmacological administration of Recently, the first selective small molecule inhibitor these compounds enhances the resolution of of NAPE-PLD, ARN19874, was reported (IC50 34 inflammation, induces satiety, and protects against µM). To identify more potent inhibitors of NAPE- the development of obesity on high fat diet (14-17). PLD, we screened compounds using a quenched In contrast, N-arachidonoyl-ethanolamide fluorescent NAPE analog, PED-A1, as a substrate for (C20:4NAE, anandamide) is a polyunsaturated NAE recombinant mouse NAPE-PLD. Screened that acts at endocannabinoid receptors (CB1 and compounds included a panel of bile acids as well as a CB2) to exert pleotropic effects on food intake, library of experimental compounds (the Spectrum anxiety, nociception, inflammation, locomotion, and Collection). Muricholic acids and several other bile memory (7,18). acids inhibited NAPE-PLD with potency similar to LCA. Fourteen potent NAPE-PLD inhibitors were Even with recent advances, much about the regulation identified in the Spectrum Collection, with the two of NAE levels and their contributions to biological most potent (IC50 ~2 μM) being symmetrically processes remains poorly understood. The first step substituted dichlorophenes: hexachlorophene and of NAE biosynthesis requires the transfer of the bithionol. Structure activity relationship assays using appropriate O-acyl chain from phosphatidylcholine additional substituted dichlorophenes identified key (PC) to the ethanolamine headgroup of a moieties needed for NAPE-PLD inhibition. Both phosphatidylethanolamine (PE) to form N-acyl- hexachlorophene and bithionol showed significant phosphatidylethanolamines (NAPEs) (19). Five selectivity for NAPE-PLD compared to non-target calcium-independent PE N-acyltransferases lipase activities such as S. chromofuscus PLD activity (PLAAT1–5) and one calcium dependent PE N- or serum lipase activity. Both also effectively acyltransferase (PLA2G4e) that catalyze this transfer 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.05.979567; this version posted March 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. have been identified in humans (19-20). The second fold specificity towards Nape-pld over other lipases step of NAE biosynthesis, conversion of NAPE to tested, and effectively inhibited NAPE-PLD in NAEs, can be directly catalyzed by NAPE HEK293 cells. phospholipase D, a member of the zinc metallo-β- lactamase family (Figure 1) (21-23). NAPE-PLD Results and discussion homologs are found in mammals, reptiles, worms, and yeast, suggesting that it has highly conserved An optimal HTS assay for changes in NAPE-PLD functions in normal physiology (12,21,24-25). activity requires high reproducibility for replicate Surprisingly, global deletion of the Nape-pld in mice samples and sufficient dynamic range to reliably from birth causes marked changes in multiple lipid detect activators and inhibitors. Fluorogenic lipid pathways yet only partially reduces NAE levels in substrates have been previously used successfully in most tissues (26,27-29). Several alternative pathways HTS assays for modulators of lipase activity (38-39). for the conversion of NAPE to NAE have now been PED-A1 is a quenched fluorogenic NAPE analog that identified (Figure 1) (24,30-31). Despite the has previously been used to measure phospholipase identification of these enzymes, how biosynthesis of A1 (PLA1) activity in vitro and in tissue samples (40). individual NAEs is controlled remains unclear. For To test if PED-A1 could be used as a substrate for instance, re-feeding of rodents leads to an increase in NAPE-PLD, we incubated PED-A1 with hexa- jejunal OEA levels, but also leads to a decrease in histidine tagged recombinant mouse Nape-pld and jejunal AEA levels (32), despite the notion that both measured the development of fluorescence. NAEs theoretically share the same biosynthetic Incubation of PED-A1 with active Nape-pld resulted machinery. Modulating the NAE-biosynthetic in a rapid rise in fluorescence while incubation with enzymes with appropriate tool compounds should Nape-pld that had been inactivated by boiling did not help elucidate the contribution of individual enzymes (See Figure S1A in Supporting Information). The KM to the biosynthesis of individual NAEs under various of recombinant Nape-pld for PED-A1 (3.0±0.5 µM) physiological and pathophysiological conditions and was determined by varying the PED-A1 could lead to the development of effective therapies concentration incubated with 0.1 µM Nape-pld (See for a range of clinical conditions including obesity, Figure S1B in Supporting Information). To ensure inflammation, chronic pain, and addiction (33-34). that the assay would tolerate small variations in buffer composition, we determined the concentration range There is currently a lack of specific inhibitors or of N-octyl-β-D-glucoside (NOG, used to stabilize activators to directly assess the contribution of Nape-pld) and DMSO (used as vehicle for PED-A1 NAPE-PLD to NAE biosynthesis under various and for screening compounds) where Nape-pld conditions. One endogenous bile acid, lithocholic activity did not differ by more than 10% from acid (LCA), has been reported to inhibit NAPE-PLD maximal activity. For NOG, this was 0.2–0.6% (w/v) (IC50 68 μM) (35). Although its bioavailability and and for DMSO this was 1.0–3.7% (v/v) (data not relatively low toxicity allow LCA to be administered shown). Based on these results, a final concentration in vivo, LCA is also a potent ligand for the bile acid of 0.4% NOG (w/v) and 1.6% DMSO (v/v) was used receptor, Tgr5, with an EC50 0.53 μM (36) so it cannot in all subsequent assays. To assess the assay’s ability be used as a selective inhibitor of NAPE-PLD. More to reproducibly distinguish between normal and recently, ARN19874 was reported to be a selective inhibited signals across replicated wells in 384-well NAPE-PLD inhibitor, with an IC50 of 34 µM (37). plate, 100 μM LCA or vehicle were added in The absorbance, distribution, metabolism, and checkerboard fashion to a 384-well plate and initial excretion (ADME) properties of this compound and rate of fluorescence change (t = 30–100s) and steady whether it has efficacy in vivo have not been reported. state fluorescence (t = 419–420s) determined (See We therefore performed high-throughput screening Figure S2 in Supporting Information). The Z’ factor (HTS) for modulators of recombinant mouse Nape- calculated for LCA (0.45–0.47) demonstrated that the pld using a small chemical library consisting of a signal windows were sufficiently separated to collection of U.S. and European drugs with known observe hits in the screen, regardless of plate position. ADME characteristics (the Spectrum Collection), and identified 14 Nape-pld inhibitors with IC50 <20 μM. LCA is currently the only known endogenous The two most potent compounds were symmetrically inhibitor of NAPE-PLD (35). There are a variety of substituted dichlorophenes which showed at least 75- primary and secondary bile acids besides LCA and 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.05.979567;
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