S-Nitrosoglutathione reductase (GSNOR) is a zinc-dependent, NAD+- and NADH-dependent, medium chain alcohol dehydrogenase (ADH) that plays an important role in nitrosative biology by metabolizing the S-nitrosothiol, GSNO. N6022 is a potent, selective and reversible GSNOR inhibitor with an IC50 of 8 nM and a Ki of 2.5 nM[3]. In cytochrome P450 assays, N6022 potently inhibited CYP2C19 with an IC50 of 0.77 μM. And it exhibited minimal cytotoxicity (IC50 > 100 μM) toward A549 epithelial lung cells. In a mouse model of ovalbumin-induced asthma, N6022 attenuated methacholine-induced broncho-constriction (airway hyperresponsiveness) in a dose- and time-dependent manner, with significant efficacy achieved with a single IV dose ≥0.01 mg/kg[4].
作用机制
N6022 binds in the GSNO substrate binding pocket like a competitive inhibitor[3].
N6022 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Beas2b cells
10 µM
12 hours
GSNO or N6022 treatment significantly alleviated CSE-induced ROS activation.
Antioxid Redox Signal. 2017 Sep 1;27(7):433-451
Beas2b cells
10 µM
12 hours
GSNO or N6022 treatment significantly inhibited CSE-induced decrease in membrane CFTR expression by rescuing it from ubiquitin-positive aggresome bodies.
Antioxid Redox Signal. 2017 Sep 1;27(7):433-451
tomato fruit cells
60 µM
12 days
Delayed tomato fruit ripening, increased total chlorophyll content by 88.57%, and reduced total carotenoid and lycopene contents
Int J Mol Sci. 2024 Feb 27;25(5):2729
N6022 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Myocardial ischemia-reperfusion injury model
Perfusion
100 nmol/L or 10 μmol/L
15 minutes prior to ischemia and 5 minutes at the start of reperfusion
To evaluate the effect of GSNO-R inhibition on myocardial ischemia-reperfusion injury. Results showed that GSNO-R inhibition reduced injury in male hearts but exacerbated injury in female hearts.
Circ Res. 2018 Nov 9;123(11):1232-1243
C57BL/6 J mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
1 mg/kg body weight
Daily starting from day 9 post-immunization
N6022 treatment ameliorated EAE clinical disease, reduced B cell infiltration into the CNS, and modulated IL-10 and IL-6 expression
Redox Biol. 2021 Sep;45:102053
Mice
Myocardial ischemia-reperfusion injury model
Perfusion
100 nmol/L or 10 μmol/L
15 minutes before ischemia and 5 minutes at the start of reperfusion
To evaluate the effect of GSNO-R inhibition on myocardial ischemia-reperfusion injury. Results showed that N6022 treatment significantly reduced injury in male hearts but exacerbated injury in female hearts.
Circ Res. 2018 Nov 9;123(11):1232-1243
Mice
Murine sickle cell disease (SCD) model
Subcutaneous injection
1 mg/kg/d
Once daily for 3 weeks
To investigate the effects of inhibiting GSNOR on vasodilation in SCD mice. Results showed that treatment with N6022 significantly improved endothelial-dependent and eNOS-dependent vasodilation in SCD mice.
Free Radic Biol Med. 2024 Mar;215:112-126
C57BL/6 mice
Chronic cigarette smoke-induced COPD-emphysema model
Intratracheal administration
4 mg/kg body weight
Three doses with a 3-day interval, for 18 weeks
GSNO or N6022 treatment significantly alleviated chronic CS-induced inflammation, aggresome formation, oxidative/nitrosative stress, apoptosis, and alveolar airspace enlargement.
Antioxid Redox Signal. 2017 Sep 1;27(7):433-451
C57BL/6J mice
Acetaminophen-induced liver injury model
Intraperitoneal injection
5 mg/kg
Single injection, duration of 10 hours
To evaluate the hepatoprotective effect of GSNOR inhibitor N6022, results showed that N6022 increased SNO-PXR levels, reduced liver necrosis and inflammatory responses.
JCI Insight. 2024 Jan 23;9(2):e172632
Mice
Gsnor−/− mice and wild-type mice
Intraperitoneal injection
5 mg/kg
To evaluate the effect of GSNOR inhibition on HSV-1 infection, results showed that N6022-treated mice were more susceptible to HSV-1 infection with higher mortality and severe immune cell infiltration in the lungs.
Redox Biol. 2021 Nov;47:102172
Female C57BL/6 mice
Experimental autoimmune encephalomyelitis (EAE)
Intraperitoneal or oral
1 mg/kg body weight (i.p.) or 2.5 mg/kg body weight (oral)
Daily treatment until the end of the study (day 41 post immunization)
To evaluate the efficacy of N6022 on EAE disease. Results showed that N6022 treatment significantly attenuated the clinical disease of EAE, inhibited the polarization and CNS effector function of proinflammatory T cells (TH1 and TH17), while inducing the polarization and function of anti-inflammatory T cells (TH2 and Treg). Additionally, N6022 treatment protected against EAE-induced demyelination.
Free Radic Biol Med. 2018 Jun;121:57-68
Tomato
Tomato fruit
Injection
60 µM
Single treatment, lasted for 12 days
Delayed tomato fruit ripening, increased endogenous NO content by 197.55% and SNOs content by 74.65%
Int J Mol Sci. 2024 Feb 27;25(5):2729
C57BL/6 mice
SARS-CoV-2 spike protein S1 domain-induced acute lung disease model
Intraperitoneal injection
1 mg/kg/day
Once daily for 5 days
To evaluate the therapeutic effects of N6022 on SARS-CoV-2 spike protein S1 domain-induced acute lung disease. Results showed that N6022 treatment significantly reduced fever and body weight loss, decreased blood levels of pro-inflammatory cytokines and coagulation factors, and reduced lung inflammatory cell infiltration and fibrin deposition.
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