Chemical Biology of Nitroxyl (HNO)

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

The chemical biology of HNO, is to determine the pharmacological and possible endogenous production of this species in vivo. One of the challenges is to determine the role that HNO may have in the biochemistry of nitric oxide synthase (NOS). In addition, we have found that NH2OH may be an important precursor to HNO under oxidative conditions. This indicates that hydroxyamic acids such as chemotherapeutic drugs hydroxyurea and SAHA may mediate some effects through HNO. Here we have investigated a variety of HNO donors and method of generation in vivo. We have currently discover a specific marker for HNO and found that it can be detected in cells. Furthermore, we have been able to determine proteomic and genomic signature that differ from HNO and NO. These finding further support our hypothesis that these species have mutually exclusive biology. We have current extended this project to better understand nitrosation and H2S as well as persulfides. In cancer, we have found that HNO will target tumor producing cell lines but not primary endothelial cells or non-tumorigenic cell lines. While in vivo these compounds are well tolerated being 20 times safer than aspirin, there is a profound selectivity in xenograph models. We are currently investigating what determines this selectivity. Furthermore we are trying to determine if these drugs can modify conventional therapy through synergism. We have begun evaluating agents that target the COVID-19 virus by developing assay of redox active agent that target critical proteins in the replication cycle of the virus. There are three critical nodes: RdRP critical in replication which is inhibited by zinc, a thiol dependent protease cathepsin and calpain that process the proteins and polyamines, arginase (zinc inhibitable) and ornithine decarboxylase (thiol susceptible to electrophilic attack). We have begun initial screening with different NO donors and HNO donors as well as H2S producing compounds.