Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities

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

doi:10.1016/j.bmcl.2011.07.103

Cited by 27 publications

(24 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

117

101

View full text Add to dashboard Cite

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.

show abstract

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

117

101

View full text Add to dashboard Cite

show abstract

“…In either case, nitric oxide is not liberated during GSNO metabolism, and the nitroso moiety is reduced, effectively removing it from the ‘NO pool.’ Strong evidence supports this as an important biological function of this protein and not simply an ex vivo activity [71] making it a novel target for therapy in some pathological conditions. [72,73]. GSNO reductase activity is influenced by both the levels of NADH and GSH; thus, the redox state of a cell may significantly impact the clearance of GSNO and the S-nitroso proteome.…”

Section: Cellular Mechanisms Of Gsno Degradationmentioning

confidence: 99%

S-Nitrosoglutathione

Broniowska

Diers

Hogg

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

320

290

View full text Add to dashboard Cite

Background S-Nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione and is thought to be a critical mediator of the down-stream signaling effects of nitric oxide (NO). GSNO has also been implicated as a contributor to various disease states. Scope of Review This review focuses on the chemical nature of GSNO, its biological activities, the evidence that it is an endogenous mediator of NO action, and implications for therapeutic use. Major Conclusions GSNO clearly exerts its cellular actions through both NO- and S-nitrosation-dependent mechanisms; however, the chemical and biological aspects of this compound should be placed in the context of S-nitrosation as a whole. General Significance GSNO is a central intermediate in formation and degradation of cellular S-nitrosothiols with potential therapeutic applications; thus, it remains an important molecule of study.

show abstract

“…Mechanistically, this increased cardioprotection has been ascribed to enhanced S-nitrosylation of HIF1α, which promotes its stabilization and transcriptional activation of VEGF [73]. Given the critical role of GSNOR in SNO homeostasis, there have been increasing efforts to develop inhibitors targeting GSNOR [74–76]. One inhibitor is in phase II clinical trials for the treatment of acute asthma.…”

Section: Denitrosylasesmentioning

confidence: 99%

Enzymatic mechanisms regulating protein S-nitrosylation: implications in health and disease

2012

View full text Add to dashboard Cite

Nitric oxide participates in cellular signal transduction largely through S-nitrosylation of allosteric and active-site cysteine thiols within proteins, forming S-nitrosoproteins (SNO-proteins). S-nitrosylation of proteins has been demonstrated to affect a broad range of functional parameters including enzymatic activity, subcellular localization, protein–protein interactions, and protein stability. Analogous to other ubiquitous posttranslational modifications that are regulated enzymatically, including phosphorylation and ubiquitinylation, accumulating evidence suggests the existence of enzymatic mechanisms for regulating protein S-nitrosylation. In particular, studies have led to the identification of multiple enzymes (nitrosylases and denitrosylases) that participate in targeted S-nitrosylation or denitrosylation of proteins in physiological settings. Nitrosylases are best characterized in the context of transnitrosylation in which a SNO-protein transfers an NO group to an acceptor protein (Cys-to-Cys transfer), but examples of transnitrosylation catalyzed by metalloproteins (Metal-to-Cys transfer) also exist. By contrast, denitrosylases remove the NO group from SNO-proteins, ultimately using reducing equivalents derived from NADH or NADPH. Here, we focus on the recent discoveries of nitrosylases and denitrosylases and the notion that their aberrant activities may play roles in health and disease.

show abstract

Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities

Cited by 27 publications

References 22 publications

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

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

S-Nitrosoglutathione

Enzymatic mechanisms regulating protein S-nitrosylation: implications in health and disease

Contact Info

Product

Resources

About