Technologies
Inhibitors of the NODs are being developed for application as microbial antibiotics, anti-tumor agents and modulators of NO signalling. The most prominent class of inhibitor of NO dioxygenase to date is imidazole antibiotics. Imidazoles have been shown to coordinate with the heme iron atom of microbial flavohemoglobin, impair ferric heme reduction, produce uncompetitive inhibition with respect to O2 and NO, and inhibit NO metabolism by yeasts and bacteria. Specifically, imidazoles bearing bulky aromatic substituents have been shown to have potential for selective and high-affinity inhibition of NO dioxygenase function by coordinating the catalytic heme iron and "fitting" within the large hydrophobic distal heme pocket. As a result, imidazole engineering has been suggested as a means to specifically inhibit NO dioxygenases.
In addition, genetically modified plants with heterologous flavohemoglobin-NODs are being developed to limit NO toxicity created by metabolism of nitrogen fertilizers by soil microbes and as a means towards plant self-fertilization through absorption of environmental NO.
Recently a lentiviral vector that allows for expression of E. coli flavoHb in mammalian cells has been described. This approach demonstrated that flavoHb is indeed enzymatically active within human and murine cells and potently blocks exogenous and endogenous sources of nitrosative stress. This technology was then extended to interrogate the role of NO synthesis in the highly tumorigenic cancer stem cells (CSCs) from human glioblastoma (brain tumor) samples. Expression of flavoHb within xenografted tumors led to depletion of NO generated by iNOS/NOS2. The phenotypic result was loss of tumorigenicity of the CSCs and improved mouse survival. These experiments demonstrate that flavoHb can be employed for in vivo studies of nitric oxide biology and suggest that therapeutic NO-depletion may be achieved via heterologous expression of bacterial flavoHbs
Read more about this topic: Nitric Oxide Dioxygenase