S-nitrosothiol (N6022) / Alpine Immune Sci, Laurel Venture Capital - LARVOL DELTA

L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice. (PubMed, Brain Dev) - "NOS inhibition may serve as a key point for further research on the progression of DMD disease and as a potential therapeutic target for this incurable disease."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Targeted Protein Degradation

Therapeutic potential of S-nitrosoglutathione reductase inhibitor in B cell-driven experimental autoimmune encephalomyelitis. (PubMed, J Neuroimmunol) - "Similar observations were made in the spinal cord, where N6022 treatment modulated B cell expression of regulatory versus effector cytokines (IL-10 > IL-6) and the expansion of regulatory versus effector T cells (Treg > Th1/Th17). These findings document that GSNOR inhibitors may potentially serve as effective immunomodulators in both T cell- and B cell-mediated EAE and multiple sclerosis."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • Solid Tumor • CD4 • IFNG • IL10 • IL17A • IL6

Opioid prescribing patterns following surgical interventions for benign prostatic hyperplasia. (PubMed, Can Urol Assoc J) - "Men undergoing BPH surgeries in OR settings were more likely to receive opioid prescriptions postoperatively, suggesting potential overprescription. Despite similar cumulative opioid use, differences in prescription rates indicate a need for improved postoperative pain management strategies, possibly using non-opioid alternatives. Future research should focus on optimizing pain control, characterizing actual opioid consumption, and considering patient-specific factors in surgical decision-making."

Journal • Benign Prostatic Hyperplasia • Pain

Novel Pathways of Oxidative and Nitrosative Inactivation of the Human MGMT Protein in Colon Cancer and Glioblastoma Cells: Increased Efficacy of Alkylating Agents In Vitro and In Vivo. (PubMed, Diseases) - " We designed a redox perturbing glutathione mimetic, a platinated homoglutathione disulfide (hGTX) by adding small amounts of cisplatin (1000:10) and used a nitric oxide-donor spermine NONOate. N6022 treatment increased the presence of nitrosylated MGMT for a longer time, thereby extending the DNA-repair deficient state both in cell culture and preclinical settings. Our findings highlight the options for redox-driven therapeutic strategies for MGMT and suggest that oxidative and/or nitrosative inactivation of DNA repair in combination with alkylating agents could be exploited."

Journal • Preclinical • Brain Cancer • CNS Tumor • Colon Cancer • Colorectal Cancer • Glioblastoma • Oncology • Solid Tumor

The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE). (PubMed, Neuroscience) - "Previously, we reported that both S-nitrosoglutathione (GSNO), a carrier of cellular nitric oxide, and N6022, an injectable form of GSNO reductase (GSNOR) inhibitor that increases endogenous GSNO levels, alleviate experimental autoimmune encephalomyelitis (EAE) in mice by suppressing Th1 and Th17 immune responses. This observation underscores the potential of increased GSNOR expression and activity as a risk factor exacerbating EAE immunopathology, while simultaneously highlighting its potential as a target for modifying the disease. Furthermore, the balanced immune regulation provided by orally active N91115 (IL-6/IL-17a vs. IL-10) presents a promising alternative to immunosuppressive drugs, reducing the risk of opportunistic infections."

Journal • CNS Disorders • Immunology • Infectious Disease • Multiple Sclerosis • IL10 • IL17A • IL6

NRT2.1 mediates the reciprocal regulation of nitrate and NO/SNO in seedling leaves of Fraxinus mandshurica and Betula platyphylla. (PubMed, Plant Physiol Biochem) - "In the present study, 25 mmol L-1 NO3- and 1 mmol L-1 NO donor sodium nitroprusside (SNP) treatment that was conducted for 24 h enhanced NO/SNO and NO3- metabolism, whereas 2.5 mmol L-1 NO3- and 80 μmol L-1 N6022 (a compound that increases SNO content) treatment reduced them in seedling leaves of Fraxinus mandshurica and Betula platyphylla. Meanwhile, FmNRT2.1 mediated NO and SNO production in seedling leaves of F. mandshurica using Agrobacterium-mediated transient transformation. These findings shed light on the reciprocal regulation between NO3- and NO/SNO in seedlings of F. mandshurica and B. platyphylla, and NRT2.1 may act as a key regulatory hub."

Journal

Nitric Oxide Synthase Modulates the S-Nitrosoglutathione Reductase Inhibitor Rescue of Neonatal Oxygen-Induced Airway Hyperreactivity in Murine Precision-cut Lung Slices (PAS 2024) - "Lung slices were pre-incubated overnight with or without a GSNOR inhibitor (N6022, 100μM) before generating MCh dose-response curves (0.25-64μM)... Neonatal hyperoxia significantly increased airway contractile responses to MCh and GSNOR inhibition attenuated AHR in the hyperoxic slices (Fig 1). Pre-incubation of hyperoxic slices with either L-NAME or DTT rendered the GSNOR inhibitor ineffective in rescuing airway responses to the maximal dose of MCh compared to vehicle (Fig 2). Conclusion(s): These studies show that neonatal hyperoxia-exposed mice display in vitro AHR to MCh and that inhibition of GSNOR attenuates oxygen-induced AHR."

Preclinical • Asthma • Bronchopulmonary Dysplasia • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis. (PubMed, Eur J Pharmacol) - "Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis."

Journal • Asthma • Cardiovascular • CNS Disorders • Immunology • Ischemic stroke • Pulmonary Disease • Reperfusion Injury • Respiratory Diseases • Vascular Neurology • GPX4 • GSTP1 • SLC7A11

The Crucial Role of SlGSNOR in Regulating Postharvest Tomato Fruit Ripening. (PubMed, Int J Mol Sci) - "In addition, the endogenous NO contents were elevated by 197.55%; 404.59%; and 713.46%, and the endogenous SNOs contents were enhanced by 74.65%; 93.49%; and 94.85%; by N6022 and GSNO treatments and SlGSNOR silencing, respectively. Altogether, these results indicate that SlGSNOR positively promotes tomato postharvest fruit ripening, which may be largely on account of its negative roles in the endogenous NO level."

Journal

Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease. (PubMed, Free Radic Biol Med) - "SS mice were treated with either phosphate-buffered saline (PBS), hE-HMGB1-BP, an hE dual-domain peptide that binds and removes HMGB1 from the circulation via the liver, 1-[4-(aminocarbonyl)-2-methylphenyl]-5-[4-(1H-imidazol-1-yl)phenyl]-1H-pyrrole-2-propanoic acid (N6022) or N-acetyl-lysyltyrosylcysteine amide (KYC) for three weeks...The marked changes in pulmonary morphometrics and GSNOR expression throughout the lung parenchyma in SS mice were improved by treating with either hE-HMGB1-BP or KYC. These data demonstrate that murine SCD induces vasculopathy and chronic lung disease by an HMGB1- and GSNOR-dependent mechanism and suggest that HMBG1 and GSNOR might be effective therapeutic targets for reducing vasculopathy and chronic lung disease in humans with SCD."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Inflammation • Pulmonary Disease • Respiratory Diseases • Sickle Cell Disease • HMGB1

Efficacies of S-nitrosoglutathione (GSNO) and GSNO reductase inhibitor in SARS-CoV-2 spike protein induced acute lung disease in mice. (PubMed, Front Pharmacol) - "Optimization of GSNO by treatment with exogenous GSNO or inhibition of GSNOR by N6022 (or GSNO knockout) protects against SP-S1-induced lung diseases in both genders. These findings provide evidence for the potential efficacies of GSNO and GSNOR inhibitors in addressing the multi-mechanistic nature of SARS-CoV-2 SP-associated acute-lung disease."

Journal • Preclinical • Cardiovascular • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • ICAM1 • IL6 • TNFA • VCAM1

Mechanistic study of the Aldo-keto reductase family 1 member A1 in regulating mesenchymal stem cell fate decision toward adipogenesis and osteogenesis. (PubMed, Life Sci) - "Several metabolism-involved regulators including Akr1A1, SIRT1, PPARγ, PGC-1α and TAZ were differentially expressed in osteoblast- and adipocyte-committed MSCs. More importantly, Akr1A1 was identified as a new key regulator for controlling the MSC lineage commitment in favor of adipogenesis but detrimental to osteogenesis. Such information should be useful to develop perspective new therapeutic agents to reverse the adipo-osteogenic differentiation of BMSCs, in a way to increase in osteogenesis but decrease in adipogenesis."

Journal • Addiction (Opioid and Alcohol) • PKM • PPARG

S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury. (PubMed, JCI Insight) - "In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations...Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation...This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention."

Journal • Hepatology • Inflammation • Liver Failure • HMGB1

GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease. (PubMed, Free Radic Biol Med) - "Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

GABA keeps nitric oxide in balance by regulating GSNOR to enhance disease resistance of harvested tomato against Botrytis cinerea. (PubMed, Food Chem) - "The endogenous NO level was excessively high after treatment with a GSNOR scavenger, N6022, making the fruit more susceptible to pathogen...However, overexpression of SlGSNOR exhibited opposite consequences. These results suggest that a suitable level of NO is beneficial for enhancing disease resistance, and GABA can help tomatoes maintain NO equilibrium by regulating GSNOR."

Journal

Fluorescein isothiocyanate, a platform for the selective and sensitive detection of S-Nitrosothiols and hydrogen sulfide. (PubMed, Talanta) - "FDTC was tested as an intracellular RSNO-sensor in germinating tomato seedlings (Solanum lycopersicum) via epifluorescence microscopy. Control plant roots exposed to FDTC showed low intracellular fluorescence which increased ∼3-fold upon exposure to extracellular S-nitrosoglutathione and ∼4-fold in the presence of N6022, a S-nitrosoglutathione reductase (GSNOR) inhibitor, demonstrating that FDTC can be used to visualize intracellular RSNO levels."

Journal

GSNOR facilitates antiviral innate immunity by restricting TBK1 cysteine S-nitrosation. (PubMed, Redox Biol) - "Concordantly, HSV-1 infection in Gsnor mice and wild-type mice with GSNOR being inhibited by N6022 resulted in higher mortality relative to the respective controls, together with severe infiltration of immune cells in the lungs. Mechanistically, GSNOR deficiency enhanced cellular TANK-binding kinase 1 (TBK1) protein S-nitrosation at the Cys423 site and inhibited TBK1 kinase activity, resulting in reduced interferon production for antiviral responses. Our study indicated that GSNOR is a critical regulator of antiviral responses and S-nitrosation is actively involved in innate immunity."

Journal • Herpes Simplex • Infectious Disease • Targeted Protein Degradation

Regulation of B cell functions by S-nitrosoglutathione in the EAE model. (PubMed, Redox Biol) - "Adoptive transfer of B cells from N6022 treated EAE mice or EAE mice deficient in the GSNOR gene also regulated T cell balance (Treg > Th17) and reduced clinical disease in the recipient EAE mice. The data presented here provide evidence of the role of GSNO in shifting B cell immune balance (IL-10 > IL-6) and the preclinical relevance of N6022, a first-in-class drug targeting GSNOR with proven human safety, as therapeutics for autoimmune disorders including multiple sclerosis."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • IL10 • IL6

GSNOR and ALDH2 alleviate traumatic spinal cord injury. (PubMed, Brain Res) - "Traumatic spinal cord injury (SCI) enhances the activity of S-nitrosoglutathione reductase (GSNOR) and inhibits the mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity, resulting in prolonged and sustained pain and functional deficits. Combining the specific inhibitor of GSNOR (N6022) with the selective activator of ALDH2 (Alda-1) provides greater protection to the neurovascular unit and confers greater functional recovery. The study is novel, and the combination therapy (N6022+Alda-1) possesses translational potential."

Journal • CNS Disorders • Complement-mediated Rare Disorders • Orthopedics • Pain • ALDH2

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia. (PubMed, BMJ Open) - "Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. Parental informed consent will be obtained. NTR6982; Pre-results."

Clinical • Journal • Gastroenterology • Hypertension • Pulmonary Arterial Hypertension

Tomato Root Growth Inhibition by Salinity and Cadmium Is Mediated By S-Nitrosative Modifications of ROS Metabolic Enzymes Controlled by S-Nitrosoglutathione Reductase. (PubMed, Biomolecules) - "Application of a GSNOR inhibitor N6022 increased both NO and S-nitrosothiol levels and stimulated root growth in both genotypes. An opposite effect occurred in cultivated S. lycopersicum, where reduced GSNOR activity and intensive S-nitrosation resulted in reduced ROS levels by abiotic stress. These data suggest stress-triggered disruption of ROS homeostasis, mediated by modulation of RNS and S-nitrosation of NADPHox and APX, underlies tomato root growth inhibition by salinity and cadmium stress."

Journal

Exogenous Nitric Oxide Enhances Disease Resistance by Nitrosylation and Inhibition of S-Nitrosoglutathione Reductase in Peach Fruit. (PubMed, Front Plant Sci) - "In this research, the effects of NO and GSNOR inhibitor (N6022) on the defense response of harvested peach fruit to Monilinia fructicola infection were investigated. Moreover, NO and GSNOR inhibitor enhanced the expression of systemic acquired resistance (SAR)-related genes, such as pathogenesis-related gene 1 (PR1), nonexpressor of PR1 (NPR1), and TGACG-binding factor 1 (TGA1). These results demonstrated that S-nitrosylation of GSNOR protein and inhibition of GSNOR activity contributed to the enhanced disease resistance in fruit."

Journal • GSR

Targeting GSNOR for functional recovery in a middle-aged mouse model of stroke. (PubMed, Brain Res) - "Daily treatment of IR animals with N6022 for 2 weeks significantly improved neurological score, brain infarctions/atrophy, survival rate, motor (measured by cylinder test) and cognitive (evaluated by novel object recognition test) functions which paralleled the decreased activity of GSNOR, reduced levels of peroxynitrite and decreased neurological score. These results are the first evidence of a new pathway for the treatment of stroke via the inhibition of GSNOR. Based on the efficacy of N6022 in the stroke animal model and its use in human therapeutic studies without toxicity, we submit that GSNOR is a druggable target, and N6022 is a promising drug candidate for human stroke therapy."

Journal • Preclinical • Acute Coronary Syndrome • Cardiovascular • Gene Therapies • Ischemic stroke • Myocardial Ischemia • Reperfusion Injury

A Safety Study Evaluating N6022 in Multiple-Ascending Doses in Healthy Subjects (clinicaltrials.gov) - P1; N=25; Completed; Sponsor: N30 Pharmaceuticals, Inc.; Phase classification: P1/2 -> P1

Phase classification • Biosimilar • Inflammation

Preclinical development of humanized CD39 and CD73 blocking antibodies targeting the ATP/adenosine immune checkpoint pathway for cancer immunotherapy (AACR 2018) - "Finally, in vivo blockade of ATP/Ado pathway in CD39ko mice resulted in improved anti-tumor efficacy of immunogenic cell death inducer chemotherapy and of immune checkpoint therapies, including PD1 and CTLA4.Taken together, these data support the clinical development of anti-CD39 and anti-CD73 neutralizing Abs for cancer immunotherapy, potentially in combination with chemotherapy or Immune Checkpoint therapy. The humanized anti-huCD39 and anti-huCD73 monoclonal antibodies are currently in preclinical development.The research leading to CD73 results were obtained within the TumAdoR collaborative consortium that received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n602200."

IO Biomarker • PD(L)-1 Biomarker • Preclinical • Oncology