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Mitigation of NADPH Oxidase 2 Activity As a Strategy to Inhibit Peroxynitrite Formation

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Mitigation of NADPH Oxidase 2 Activity As a Strategy to Inhibit Peroxynitrite Formation Mitigation of NADPH Oxidase 2 Activity as a Strategy to Inhibit Peroxynitrite Formation Jacek Zielonka, Monika Zielonka, Lynn Verplank, Gang Cheng, Micael Hardy, Olivier Ouari, Mehmet Menaf Ayhan, Radoslaw Podsiadly, Adam Sikora, J Lambeth, et al. To cite this version: Jacek Zielonka, Monika Zielonka, Lynn Verplank, Gang Cheng, Micael Hardy, et al.. Mitigation of NADPH Oxidase 2 Activity as a Strategy to Inhibit Peroxynitrite Formation. Journal of Biologi- cal Chemistry, American Society for Biochemistry and Molecular Biology, 2016, 291, pp.7029-7044. 10.1074/jbc.M115.702787. hal-01400640 HAL Id: hal-01400640 https://hal-amu.archives-ouvertes.fr/hal-01400640 Submitted on 28 Nov 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. JBC Papers in Press. Published on February 2, 2016 as Manuscript M115.702787 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M115.702787 Nox2 inhibition as anti-nitration strategy Mitigation of NADPH oxidase 2 activity as a strategy to inhibit peroxynitrite formation Jacek Zielonka1, Monika Zielonka1, Lynn VerPlank2, Gang Cheng1, Micael Hardy3, Olivier Ouari3, Mehmet Menaf Ayhan3, Radosław Podsiadły1,4, Adam Sikora5, J. David Lambeth6, Balaraman Kalyanaraman1 1From the Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226 2The Broad Institute of MIT and Harvard, Cambridge, MA 02142 3Aix-Marseille Université, CNRS, ICR UMR 7273, 13397 Marseille, France 4Institute of Polymer and Dye Technology, Faculty of Chemistry, Lodz University of Technology, Stefanowskiego 12/16, 90-924 Lodz, Poland 5 Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Downloaded from Żeromskiego 116, 90-924 Lodz, Poland 6Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 *Running title: Nox2 inhibition as anti-nitration strategy http://www.jbc.org/ To whom correspondence should be addressed: Jacek Zielonka, PhD or Balaraman Kalyanaraman, PhD, Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, Tel: (414) 955-4000; Fax: (414) 955-6512; Email: [email protected] or [email protected] by guest on November 22, 2016 Keywords: reactive nitrogen species, reactive oxygen species, fluorescence probes, NADPH oxidase inhibitors, high-throughput screening (HTS), superoxide radical anion, hydrogen peroxide, peroxynitrite •– ABSTRACT formed from Nox2-derived O2 and nitric oxide Using a high-throughput screening synthase (NOS)-derived nitric oxide. (HTS)-compatible assays for superoxide and hydrogen peroxide, we identified potential INTRODUCTION inhibitors of NADPH oxidase (Nox2) isoform NADPH oxidase (Nox) enzymes (Nox1-5, from a small library of bioactive compounds. Duox1/2) have been proposed as potential By using multiple probes (hydroethidine, therapeutic targets in the treatment of a variety of hydropropidine, Amplex Red, and coumarin inflammatory and fibrotic diseases including boronate) with well-defined redox chemistry cancer (1-3). Unlike other redox-active enzymes that form highly diagnostic marker products for which generation of reactive oxygen species •– upon reaction with superoxide (O2 ), hydrogen (ROS) is an “accidental” byproduct of their – peroxide (H2O2), and peroxynitrite (ONOO ), primary catalytic function, the only known the number of false positives was greatly function of Nox enzymes is generation of ROS •– decreased. Selected hits for Nox2 were further (e.g., O2 and H2O2) (Fig. 1) (4;5). Several Nox – •– screened for their ability to inhibit ONOO isoforms including Nox2 form both O2 and H2O2 •– formation in activated macrophages. New (via dismutation of O2 ), with the exception of – diagnostic marker product for ONOO is Nox4 which generates primarily H2O2 with little or •– reported. We conclude that the newly no detectable O2 (4;5). A major impediment to developed HTS/ROS assays could also be used advancing Nox research is the paucity of selective to identify potential inhibitors of ONOO– 1 Copyright 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Nox2 inhibition as anti-nitration strategy inhibitors of Nox isoforms, including Nox1 and 2 also use these candidate inhibitors of Nox2 as (6). This is in part due to the lack of reliable and potential inhibitors of ONOO– generated via Nox2 high-throughput-compatible detection probes and intermediacy. •– assays that are specific for O2 and H2O2. With the recent discovery of new probes with well-defined EXPERIMENTAL PROCEDURES redox chemistry that form highly diagnostic Materials ̶ All compounds in the HTS marker products upon reaction with ROS/RNS library were routinely dissolved in DMSO and both under in vitro and in vivo conditions and stored at -20C. DMSO concentration (<1%) high-throughput global profiling assays (Table 1) was kept the same in both control and treatment (7), we can now screen a small library of bioactive conditions. In confirmatory studies, stock compounds. One of the objectives of this study is solutions were prepared at higher concentrations to identify small molecule inhibitors of Nox2 (typically 10 mM or higher), such that the final isoform using the high-throughput screening concentration of the solvent vehicle was kept (HTS)/ROS based assay(s) that largely eliminate minimal (<0.3% v/v) upon dilution. false positives. Previously, we reported the power Hydropropidine (HPr+), coumarin boronic acid of our newly-developed HTS/ROS assays in (CBA), and ortho-mito-phenylboronic acid (o- identifying true “hits” for Nox2 inhibition and MitoPhB(OH)2) were synthesized according to Downloaded from eliminating false positives at the outset (8). published procedures (19-22). Deuterated (d15) Typically, the chemiluminescent probe, L-012, has analogs of o-MitoPhB(OH)2 and o-MitoPhNO2 been used in Nox assay (9). Comparison between were synthesized in the analogous protocol to o- L-012 assay and our HTS/ROS assay revealed that MitoPhB(OH)2 but using deuterated http://www.jbc.org/ L-012 increased false positives by at least a factor triphenylphosphine (d15-PPh3), while d15-o- of 4, and that this increase is due to inhibition of MitoPhOH was synthesized by oxidation of d15-o- peroxidase enzyme used in the L-012/Nox assay MitoPhB(OH)2 by excess H2O2. Amplex Red (10- (10). A related objective of this study is also to acetyl-3,7-dihydroxyphenoxazine), resorufin, and identify new small molecule inhibitors of RNS 7-hydroxycoumarin were purchased from Cayman (e.g., peroxynitrite). Peroxynitrite (ONOO–) is a and Sigma-Aldrich. Hydroethidine (HE) was from by guest on November 22, 2016 potent oxidizing and nitrating species formed from Invitrogen. Authentic standards of 2- •– + a diffusion-controlled reaction between O2 and hydroxyethidium (2-OH-E ) and 2- nitric oxide (•NO) (11;12) (Fig. 1), and has been hydroxypropidium (2-OH-Pr++) were synthesized implicated in various neurodegenerative and as described previously (19;23;24). Stock cardiovascular diseases (13-15). Although ongoing solutions of CBA, HE and Amplex Red were efforts focus on antinitration strategies mostly prepared at 20-100 mM concentration in DMSO – through direct scavenging of ONOO and/or and stored at -80C. For experiments involving related species (16), a better approach is to HOCl, DMSO was replaced with ethanol. •– suppress the sources of generation of O2 (Nox) Horseradish peroxidase (HRP, type VI), and/or inhibition of nitric oxide synthase, superoxide dismutase (SOD), catalase (CAT) and particularly inducible nitric oxide synthase (iNOS) all other reagents were obtained from Sigma- (Fig. 1) (17;18). In this study, we identified Aldrich. several candidate Nox2 inhibitors through HTS- For organic synthesis, THF was distilled based ROS assays from testing a library of >2,000 under dry argon atmosphere in the presence of bioactive compounds at the Broad Institute. sodium and benzophenone. All reagents were used Selected hits for Nox2 inhibition were further as received without further purification. The tested for inhibition of ONOO– formation in reactions were monitored by TLC on silica gel activated macrophages. Results suggest that the Merck 60F254. Crude materials were purified by HTS/ROS strategy developed herein could be used flash chromatography on Merck Silica gel 60 – to identify Nox2 inhibitors that inhibit ONOO (0.040-0.063 mm). 31P NMR, 1H NMR and 13C formation. In this study we also discovered a new NMR spectra were recorded with Bruker DPX 300 diagnostic marker product for specific detection or 400 spectrometers at 121.49, 300.13 and 75.54 and quantitation of peroxynitrite in biological MHz, respectively. 31P NMR measurements were systems. One of the objectives of this study is to carried out in CDCl3 using 85% H3PO4 as an 2 Nox2 inhibition as anti-nitration strategy external standard with broad-band 1H decoupling. where control+ and control– correspond to PMA- 1H NMR and 13C NMR measurements were stimulated cells in the presence of DMSO only or carried out in CDCl3 using TMS or CDCl3
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