Cellular levels of SNOs are controlled by the enzyme S-nitrosoglutathione reductase (GSNOR
) through the process of de-nitrosylation (Malik et al., 2011).
N91115 works through a novel mechanism of action called S-nitrosoglutathione reductase (GSNOR
) inhibition that is presumed to modulate the unstable and defective CFTR protein responsible for CF.
Pathophysiology is correlated with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to not only the loss of or enhanced nitric oxide synthase activity but also the denitrosylation by a major denitrosylase, S-nitrosoglutathione reductase (GSNOR) .
Liu, "S-nitrosylation from GSNOR deficiency impairs DNA repair and promotes hepatocarcinogenesis," Science Translational Medicine, vol.
The discovery of denitrosating enzymatic systems, namely, those dependent on thioredoxin 1 (Trxl) and S-nitrosoglutathione reductase (GSNOR
) activities, which actively participate the S-nitrosothiol-to-sulfhydryl (SNO-to-SH) reduction [16-19] (Figure 1), definitively sealed the importance of S-nitrosation in cell physiology and human health (Table 1).
N6022, a first-in-class inhibitor of s-nitrosoglutathione reductase (GSNOR
), has the potential to be an important new treatment for acute exacerbations of asthma, chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease (IBD), the company said.