Discovery of <i>S</i>-Nitrosoglutathione Reductase Inhibitors: Potential Agents for the Treatment of Asthma and Other Inflammatory Diseases

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

doi:10.1021/ml200045s

Cited by 51 publications

(60 citation statements)

References 33 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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“…Based on the importance of GSNOR in cellular GSNO homeostasis, next, we evaluated the efficacy of endogenous GSNO using N6022, a first-in-class inhibitor of GSNO catabolizing enzyme GSNOR in EAE disease. GSNOR inhibitors are being tested for clinical use for asthma and cystic fibrosis [70]. Among these, N6022 is the best characterized and its safety was proven by Phase I and II studies [50].…”

Section: Discussionmentioning

confidence: 99%

S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis

Saxena

Won

Choi

et al. 2018

Free Radical Biology and Medicine

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We previously reported that S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, attenuated TH17-mediated immune responses in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Cellular GSNO homeostasis is regulated via its synthesis by reaction between nitric oxide and glutathione and its enzymatic catabolism by GSNO reductase (GSNOR). In this study, we evaluated potential of reversible inhibitor of GSNOR (N6022) in comparison with exogenous GSNO in immunopathogenesis of EAE. Daily treatment of EAE mice with N6022 or exogenous GSNO significantly attenuated the clinical disease of EAE, but N6022 treatment showed greater efficacy than GSNO. Both N6022 and exogenous GSNO treatments increased the spleen levels of GSNO, as documented by increased protein-associated S-nitrosothiols, and inhibited polarization and CNS effector function of proinflammatory TH17 cells while inducing the polarization and CNS effector function of anti-inflammatory CD4+ CD25+ FOXP3− regulatory T (Treg) cells. Moreover, N6022 further attenuated TH1 while inducing TH2 and CD4+ CD25+ FOXP3+ Treg in their polarization and CNS effector functions. Similar to GSNO, the N6022 treatment protected against the EAE disease induced demyelination. However, neither exogenous GSNO nor N6022 treatment did not cause significant systemic lymphopenic effect as compared to FTY720. Taken together, these data document that optimization of cellular GSNO homeostasis by GSNOR inhibitor (N6022) in NO metabolizing cells attenuates EAE disease via selective inhibition of pro-inflammatory subsets of CD4+ cells (TH1/TH17) while upregulating anti-inflammatory subsets of CD4+ cells (TH2/Treg) without causing lymphopenic effects and thus offers a potential treatment option for MS/EAE.

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“…S-nitrosoglutathione (GSNO) is thought to play an important role in regulating nitric oxide-containing species and influencing the airway smooth muscle tone. 36 In mice, the deletion of GSNOR has been shown to reduce airway hyperreactivity. 36 GSNO levels are decreased in CF, and increased GSNO in vitro has been shown to increase F508del-CFTR expression and function.…”

Section: Protein Repair In F508del Homozygotesmentioning

confidence: 99%

“…36 In mice, the deletion of GSNOR has been shown to reduce airway hyperreactivity. 36 GSNO levels are decreased in CF, and increased GSNO in vitro has been shown to increase F508del-CFTR expression and function. 37 This observation has led to an interest in GSNOR inhibitors as potential CFTR modulators in addition to their anti-inflammatory properties.…”

Section: Protein Repair In F508del Homozygotesmentioning

confidence: 99%

Protein Repair

Espel¹,

Jain

2015

Clinical Pulmonary Medicine

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Cystic fibrosis (CF) is a genetic disease caused by a variety of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which leads to either an absent or a dysfunctional CFTR protein. The specific mechanism of protein dysfunction is dependent on the specific underlying mutation, but can be broadly defined into 5 functional classes. Recent advances in CF therapeutics have focused on the development of drugs targeting the underlying CFTR protein defect to treat the disease (CFTR modulators). In particular, ivacaftor has successfully shown improvements in a subset of CF patients on a variety of clinical outcomes, including a >10% absolute improvement in forced expiratory volume in 1 second. Ivacaftor is the first CFTR modulator approved for the treatment of CF, but its approved indications cover <5% of the CF patients in the United States. However, other drugs are in development, which provide benefit to the >90% of the CF patients with mutations not presently covered by ivacaftor.

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Discovery of S-Nitrosoglutathione Reductase Inhibitors: Potential Agents for the Treatment of Asthma and Other Inflammatory Diseases

Cited by 51 publications

References 33 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 (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis

Protein Repair

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