Structure–activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement

Sun, Xicheng; Qiu, Jian; Strong, Sarah A.; Green, Louis S.; Wasley, Jan W. F.; Colagiovanni, Dorothy B.; Mutka, Sarah C.; Blonder, Joan P.; Stout, Adam M.; Richards, Jane P.; Chun, Lawrence; Rosenthal, Gary J.

doi:10.1016/j.bmcl.2011.04.086

Cited by 19 publications

(13 citation statements)

References 31 publications

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“…As compared to genetic tools such as the GSNOR −/− mouse, newly discovered GSNOR inhibitors 17, 58, 59 should enable the investigation of S-nitrosylation-based signaling in a wider variety of biological contexts. More importantly, these compounds also have potential utility as therapeutics in pulmonary and cardiovascular diseases 12, 13 , and thus there is a growing need to assess their global effects.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Characterization of the Cellular Response to Nitrosative Stress Mediated by S-Nitrosoglutathione Reductase Inhibition

Foster¹,

Yang²,

Gooden³

et al. 2012

J. Proteome Res.

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The S-nitrosoglutathione-metabolizing enzyme, GSNO reductase (GSNOR), has emerged as an important regulator of protein S-nitrosylation. GSNOR ablation is protective in models of asthma and heart failure, raising the idea that GSNOR inhibitors might hold therapeutic value. Here, we investigated the effects of a small molecule inhibitor of GSNOR (GSNORi) in mouse RAW 264.7 macrophages. We found that GSNORi increased protein S-nitrosylation in cytokine-stimulated cells, and we utilized stable isotope labeling of amino acids in cell culture (SILAC) to quantify the cellular response to this “nitrosative stress”. The expression of several cytokine-inducible immunodulators, including osteopontin, cyclooxygenase-2 and nitric oxide synthase isoform 2 (NOS2) were decreased by GSNORi. In addition, selective targets of the redox-regulated transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)—including heme oxygenase 1 (HO-1) and glutamate cysteine ligase modulatory subunit—were induced by GSNORi in a NOS2- and Nrf2-dependent manner. In cytokine-stimulated cells, Nrf2 protected from GSNORi-induced glutathione depletion and cytotoxicity, and HO-1 activity was required for downregulation of NOS2. Interestingly, GSNORi also affected a marked increase in NOS2 protein stability. Collectively, these data provide the most complete description of the global effects of GSNOR inhibition and demonstrate several important mechanisms for inducible response to GSNORi-mediated nitrosative stress.

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Section: Discussionmentioning

confidence: 99%

Proteomic Characterization of the Cellular Response to Nitrosative Stress Mediated by S-Nitrosoglutathione Reductase Inhibition

Foster¹,

Yang²,

Gooden³

et al. 2012

J. Proteome Res.

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“…Due to the drug’s modest bioavailability (~10%) 52 , its potential as a marketable tocolytic remains in question. However, numerous derivatives of N6022 have been identified 53 as well as other compounds targeting GSNOR 40 that may prove useful as tocolytic agents. Beyond GSNOR, there are other NO-mediators in the cell such as the thioredoxin system 54 and carbonyl reductase 27 that may also prove attractive as therapeutic targets to increase the availability of critical protein S-nitrosations in the cell.…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosoglutathione Reductase Underlies the Dysfunctional Relaxation to Nitric Oxide in Preterm Labor

Barnett

Smith

Ulrich

et al. 2018

Sci Rep

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Tocolytics show limited efficacy to prevent preterm delivery. In uterine smooth muscle cGMP accumulation following addition of nitric oxide (NO) has little effect on relaxation suggesting a role for protein S-nitrosation. In human myometrial tissues from women in labor at term (TL), or spontaneously in labor preterm (sPTL), direct stimulation of soluble guanylyl cyclase (sGC) fails to relax myometrium, while the same treatment relaxes vascular smooth muscle completely. Unlike term myometrium, effects of NO are not only blunted in sPTL, but global protein S-nitrosation is also diminished, suggesting a dysfunctional response to NO-mediated protein S-nitrosation. Examination of the enzymatic regulator of endogenous S-nitrosoglutathione availability, S-nitrosoglutathione reductase, reveals increased expression of the reductase in preterm myometrium associated with decreased total protein S-nitrosation. Blockade of S-nitrosoglutathione reductase relaxes sPTL tissue. Addition of NO donor to the actin motility assay attenuates force. Failure of sGC activation to mediate relaxation in sPTL tissues, together with the ability of NO to relax TL, but not sPTL myometrium, suggests a unique pathway for NO-mediated relaxation in myometrium. Our results suggest that examining the action of S-nitrosation on critical contraction associated proteins central to the regulation of uterine smooth muscle contraction can reveal new tocolytic targets.

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“…GSNOR inhibition increases GSNO availability in the cell and in turn facilitates •NO-mediated signaling pathways. Dozens of small molecules have been identified that can inhibit GSNOR to varying degrees (Green et al, 2012; Jiang et al, 2016; Sanghani et al, 2009; Sun et al, 2012, 2011a, 2011b). Two of these, N6022 (3-(5-(4-(1H-imidazol-1-yl) phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl) propionic acid) and N91115 from Nivalis Pharmaceuticals show promise as potentially safe and effective GSNOR inhibitors that have undergone clinical trial for both the treatment of mild asthma (clinicaltrials.gov - NCT01316315), and cystic fibrosis in individuals who are heterozygous for the cystic fibrosis transmembrane conductance regulator (CFTR) gating mutation CFTRΔF508+ (clinicaltrials.gov – N6022: NCT01746784; N91115: NCT02724527).…”

Section: Therapeutic Inhibition Of Gsnormentioning

confidence: 99%

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

Barnett

Buxton

2017

Critical Reviews in Biochemistry and Molecular Biology

119

101

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S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

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Structure–activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement

Cited by 19 publications

References 31 publications

Proteomic Characterization of the Cellular Response to Nitrosative Stress Mediated by S-Nitrosoglutathione Reductase Inhibition

Proteomic Characterization of the Cellular Response to Nitrosative Stress Mediated by S-Nitrosoglutathione Reductase Inhibition

S-Nitrosoglutathione Reductase Underlies the Dysfunctional Relaxation to Nitric Oxide in Preterm Labor

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

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