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  • Review Article
  • Published:

Sod mimetics are coming of age

Nature Reviews Drug Discovery volume 1, pages 367–374 (2002)Cite this article

Key Points

  • Under normal circumstances, formation of superoxide anions is kept under tight control by superoxide dismutase enzymes. These include the manganese (Mn) enzyme in mitochondria and the copper (Cu)/zinc (Zn) enzyme that is present in the cytosol or on extracellular surfaces.

  • Superoxide anions are formed by means of several pathways, including through normal cellular respiration, by inflammatory cells, by endothelial cells and in the metabolism of arachidonic acid.

  • Extensive scientific research over the past twenty years has shown that, in acute and chronic inflammation, superoxide anions are produced at a rate that overwhelms the capacity of the endogenous superoxide dismutase enzyme-defence system to remove them. Such an imbalance results in superoxide-mediated damage.

  • Protective and beneficial roles of superoxide dismutase have been shown in a broad range of diseases, both preclinically and clinically. The results from the latter studies prove the concept that superoxide anions have an important role in human disease, and that their removal by the native enzyme does in fact result in beneficial outcomes.

  • Although the native enzymes have shown promising anti-inflammatory properties in both preclinical and clinical studies in various diseases, there were drawbacks and issues that were associated with the use of the native enzymes as therapeutic agents and as pharmacological tools.

  • On the basis that removing superoxide anions modulates the course of inflammation, synthetic, low-molecular-mass mimetics of the superoxide dismutase enzymes, which can overcome some of the limitations that are associated with the use of the native enzymes, have been developed as potential therapeutic agents.

Abstract

The list of pathophysiological conditions that are associated with the overproduction of superoxide anions expands every day. The most exciting realization is that there seems to be a similarity between the tissue injury that is observed in various disease states, as superoxide anions produce tissue injury and associated inflammation in all tissues in similar ways. Tissue injury and inflammation form the basis of many disease pathologies, including ischaemia and reperfusion injuries, radiation injury, hyperoxic lung damage and atherosclerosis. This commonality provides a unique opportunity to manipulate numerous disease states with an agent that removes superoxide anions.

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Figure 1: Biochemical effects of superoxide generation.
Figure 2
Figure 3: Structure and characteristics of M40403.
Figure 4: Proposed scheme of some of the potential sites for the protective actions of M40403.

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Authors and Affiliations

  1. MetaPhore Pharmaceuticals, 1910 Innerbelt Business Center Drive, St Louis, 63114, Missouri, USA

    Daniela Salvemini & Dennis P. Riley

  2. Institute of Pharmacology, University of Messina, Messina, Italy

    Salvatore Cuzzocrea

Authors
  1. Daniela Salvemini
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  2. Dennis P. Riley
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  3. Salvatore Cuzzocrea
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Correspondence to Daniela Salvemini.

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DATABASES

LocusLink

ICAM1

IL-1β

IL-6

IL-10

NF-κB

PARP

P-selectin

SOD1

Sod1

SOD2

Sod2

SOD3

Sod3

TNF-α

xanthine oxidase

OMIM

Crohn's disease

osteoarthritis

Parkinson's disease

rheumatoid arthritis

LINKS

Metaphore Pharmaceuticals

Glossary

ENZYME MIMETIC

A chemical entity that exactly copies the functional property of an enzyme.

DISMUTATION

A chemical reaction in which two molecules of the same compound react together to produce two new molecules.

NEUTROPHILS

Circulating white blood cells in the granulocyte series that represent from 55–65% of the total number of leukocytes.

HYPOTENSION

Subnormal arterial blood pressure.

REDUCING EQUIVALENT

A reducing agent that provides a source of electrons.

METALLOPORPHYRIN

A metal complex with a porphyrin ligand — a completely unsaturated macrocyclic tetrapyrrole ligand that contains a π-conjugated ring system of the class that includes the iron-containing oxygen-binding site (haem) of haemoglobin.

FREE RADICAL

Any species capable of independent existence that contains one or more unpaired electrons — an unpaired electron being one that is alone in an orbital.

CATALASE

A haem-containing protein (enzyme) that catalytically converts hydrogen peroxide to water and dioxygen.

CARRAGEENAN

The name given to a family of sulphated polysaccharides that are obtained from various seaweeds.

REACTIVE OXYGEN SPECIES

These include O2●−, OH and H2O2, as well as unstable intermediates that are produced during the peroxidation of lipids.

CYCLIC VOLTAMETRY EXPERIMENT

A standard electrochemical technique for measuring oxidation.

INTRA-ARTICULAR INJECTION

An injection into the articular space.

ELECTROPARAMAGNETIC RESONANCE

(EPR). A name applied to a routine technique that is used to study molecules and ions that contain unpaired electrons by observing the magnetic fields at which they are in resonance with monochromatic radiation.

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Salvemini, D., Riley, D. & Cuzzocrea, S. Sod mimetics are coming of age. Nat Rev Drug Discov 1, 367–374 (2002). https://doi.org/10.1038/nrd796

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