The first goal of the current article is to give an overview of the biochemistry and the pathophysiological actions of peroxynitrite (ONOO−), a short-lived oxidant species formed by the diffusion-controlled reaction of nitric oxide (•NO) with a superoxide radical (O2•−). The second goal of the article is to outline the therapeutic implications of peroxynitrite, and to give an overview of the various pharmacological classes of peroxynitrite scavengers and peroxynitrite decomposition catalysts.
Peroxynitrite induces cell death, and can influence signal-transduction processes, mitochondrial function and signalling of apoptosis. The formation and reactions of peroxynitrite play a significant role in various diseases. Products of peroxynitrite reactions with macromolecules have been detected in several pathophysiological conditions, including vascular diseases, ischaemia–reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration. In these conditions, pharmacological inhibition of the formation or action of peroxynitrite was shown to be of benefit.
The biological chemistry of peroxynitrite is highly pH-dependent and is dictated primarily by reactions with thiols, carbon dioxide and transition-metal centres. Reaction of peroxynitrite and/or peroxynitrite-derived radicals (for example, carbonate and nitrogen dioxide radicals) with targets results in one- and two-electron oxidations and nitration. Diffusion of peroxynitrite through biomembranes can cause oxidative damage at one to two cell diameters from its site of formation.
The most advanced pharmacological strategies to attenuate the toxic effects of peroxynitrite involve its fast (k>1 × 106 M−1s−1) catalytic reduction to nitrite (NO2) or its isomerization to nitrate (NO3) by metalloporphyrins. Manganese and iron metalloporphyrinic compounds have been shown to rapidly react with peroxynitrite and promote its decomposition in a catalytic fashion. Such compounds — including manganese (III) meso-tetrakis((N-ethyl) pyridynium-2-yl) l porphyrin (MnTE-2-PyP), manganese (III) tetrakis(N-N′-diethylimidazolium-2-yl)porphyrin (AEOL-10150) and FeCl tetrakis-2-(triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) — attenuate peroxynitrite-dependent toxicity in vitro and in vivo, and emerge as candidates for drug development for the therapy of cardiovascular, inflammatory and neurodegenerative diseases.
Peroxynitrite — the product of the diffusion-controlled reaction of nitric oxide with superoxide radical — is a short-lived oxidant species that is a potent inducer of cell death. Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia–reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration. In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite. These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
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We thank V. Valez and D. Vitturi (Universidad de la República, Uruguay) for their contribution to the artwork. We also thank G. Ferrer-Sueta (Universidad de la República, Uruguay) for useful discussions. This work was supported by the NIH R01 GM060915 grant and the Oscar Asboth Project Grant from the National Office of Research and Technology, Budapest, Hungary to C.S.; HL54926, AG13966, ES013508 NIEHS Center of Excellence in Environmental Toxicology grants to H.I.; and The Howard Hughes Medical Institute and the International Centre of Genetic Engineering and Biotechnology grant to R.R. H.I. is the Gisela and Dennis Alter Chair in Pediatric Neonatology at the Children's Hospital of Philadelphia. R.R. is a Howard Hughes International Research Scholar.
C.S. is a founder, stockholder and consultant to Inotek Pharmaceuticals Corporation, a pharmaceutical firm that is involved in the development of peroxynitrite decomposition catalysts.
- Nitric oxide
The product of nitric oxide (•NO) synthases, a family of proteins that catalyze the oxidation of the guanidine group of L-arginine to citrulline and •NO.
The product of the one-electron reduction of molecular oxygen.
- Transition metal centres
Complexes of biomolecules with transition metals such as iron, manganese or copper that can participate in redox chemistry.
- Radical–radical termination
A reaction between two free radicals, which leads to a non-free radical adduct as a reaction product and therefore stops radical propagation reactions.
- Homolytic fission
Rupture of a covalent bond in a molecule, in which the two resulting products keep one of the bond electrons (for example, A:B → A. + B.).
A cofactor that carries electrons for redox reactions. It serves as a cofactor for nitric oxide synthase.
- Mitochondrial electron-transport chain
A series of redox carrier proteins in the inner mitochondrial membrane that enable the flow of electrons from respiratory substrates to molecular oxygen. The potential energy inherent in the electron gradient is used to drive the synthesis of ATP when protons flow back across the membrane through another enzyme complex, ATP synthase.
- Cytochrome c
An evolutionally highly conserved small 12,000 daltons haem protein present in the mitochondrial intermembrane space. It participates in mitochondrial electron transport and can also serve as a pro-apoptotic signal if released into the cytosol.
- Mn superoxide dismutase
A key manganese-containing mitochondrial antioxidant enzyme that catalyzes superoxide radical dismutation.
- Poly(ADP-ribose) polymerase
(PARP). Several reactive oxygen and nitrogen species can trigger DNA strand breakage, which then activates the nuclear enzyme PARP. Rapid activation of the enzyme depletes the intracellular concentration of its substrate, NAD, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. PARP plays a physiological role in the cells to facilitate DNA repair and to maintain genomic integrity.
- Permeability transition pore
A mitochondrial multiprote in structure that once activated serves for the release of pro-apoptotic factors into the cytosol.
A serious systemic inflammatory disease condition associated with fever, elevated white blood cell count, raised heart rate and increased breathing rate. Severe sepsis can be also associated with multiple organ failure and circulatory collapse.
A macrocyclic organic molecule consisting of four pyrrole rings that participates in the structure of haem proteins such as haemoglobin and cytochromes. It can tightly bind iron and manganese.
A group of endogenous amines (adrenaline, noradrenaline and dopamine) derived from catechol that have important physiological effects as neurotransmitters and hormones. Some of their effects include increases in heart rate, blood pressure and blood glucose levels.
A molecule that has the capacity of tight metal binding (complexation).
A chemical reaction between two identical molecules to produce two different products (for example, superoxide dismutation to molecular oxygen and hydrogen peroxide).
- Cage return reaction
In the course of a chemical reaction, the reaction between two transient products before they diffuse out of the 'solvent cage'.
A type of stereoisomerism that may arise in systems in which free rotation around a single covalent bond is impeded sufficiently so as to allow different stereoisomers to be isolated.
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Szabó, C., Ischiropoulos, H. & Radi, R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6, 662–680 (2007). https://doi.org/10.1038/nrd2222
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