GSNO and GSNOR
Endogenous S-nitrosoglutathione (GSNO) plays a critical role in modulating protein function through the transfer of nitric oxide to a protein thiol group, or S-nitrosation.. Although administering GSNO directly has shown potential as a therapeutic intervention in preclinical models of cystic fibrosis and other diseases, it is limited as a chronic therapy for several reasons including difficulty in formulation and administration.
Depleted GSNO levels are believed to contribute to loss of airway function and pathology in CF lung disease due to dysregulated S-nitrosation. The S-nitrosation of certain proteins has been shown to modulate CFTR activity and decrease inflammation in preclinical human airway and animal models of disease. These targeted effects have been demonstrated to modify certain molecular chaperones, such as Hsp70/Hsp90 organizing protein or HOP which affect trafficking and stability of the F508del CFTR protein.
GSNO concentrations are regulated by GSNO reductase (GSNOR) an enzyme that breaks down GSNO. GSNOR, through its regulation of GSNO levels, plays a key role in pulmonary, gastrointestinal, and cardiovascular physiology and pathophysiology.
The Nivalis drug development strategy is based on the premise that the inhibition of GSNOR will increase intracellular levels of GSNO by preventing its degradation, particularly in the setting of cystic fibrosis and other diseases that have decreased levels of GSNO and/or increased GSNOR.