Nitroxyl (HNO) (HNO)

Nitroxyl (HNO), also known as azanone, is the one-electron reduced and protonated form of nitric oxide and serves as a highly reactive nitrogen species that targets a broad range of cellular macromolecules. Its primary biological activity stems from its high affinity for thiols, leading to the post-translational modification of cysteine residues in proteins such as the ryanodine receptor (RyR2), SERCA2a, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Fukuto et al., 2005). These interactions can modulate cardiac contractility or, at higher concentrations, disrupt metabolic pathways and induce oxidative stress. Furthermore, HNO is known to interact with DNA, causing strand breaks and cross-linking, which contributes to its cytotoxic profile in malignant cells (Ohshima et al., 1999). While HNO donors like Cimlanod have been investigated for treating acute decompensated heart failure due to their positive inotropic and lusitropic effects, the broad and non-specific nature of HNO's cytotoxic interactions with DNA and proteins presents both a therapeutic opportunity for oncology and a significant safety challenge (Cowart et al., 2019). The rapid reaction of HNO with endogenous antioxidants like glutathione further complicates its delivery and necessitates the use of specialized donor molecules to achieve therapeutic levels at the intended site of action.

Other names

AzanoneHydrogen nitrosylNitrosyl hydrideReduced nitric oxide

Nitroxyl donors release HNO, which acts as an electrophile to modify cysteine thiols on proteins, forming N-hydroxysulfenamides or disulfides, and reacts with DNA to cause oxidative damage and strand breaks (Fukuto et al., 2005; Ohshima et al., 1999).