Российская академия наук

Anti-inflammatory drugs having endothelium-protective and immune-modulating features based on modified antioxidative enzymes

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Anti-inflammatory drugs having endothelium-protective and immune-modulating features based on modified antioxidative enzymes

Novoselov. V.I., Volkova A.G., Palutina O.A. Sharapov M.G.

Institute of Cell Biophysics, RAS, Pushchino, Russia, e-mail: novoselov-vi@rambler.ru

It is known that different in origin inflammatory diseases in humans have two main features that appear in all types of inflammation, namely oxidative stress and immune imbalance. Indeed, inflammation is attended by a strong oxidative stress, which is one of the main factors affecting, especially in epithelial tissues. Is especially true in case of burns of varying origins, acute inflammation caused by bacterial endotoxins, and so on. A similar pattern is observed during ischemia in isolated organs (for example, during reperfusion and in transplantation of organs). In

these cases, under conditions of oxidative stress, endogenous cell defense system operates including both antioxidant enzymes and low molecular weight compounds, but it is not able to fully perform of its function by neutralizing excess reactive oxygen species and the treatment requires the use of powerful exogenous antioxidants.

On the other hand, an imbalance in the immune system inflammation is manifested as extremely high secretion of pro-inflammatory cytokines that enhance overall intoxication. In the tissues of the inflammation-bearing body, an excessive activation of protective systems (increased production of cytokines, stress proteins, nitric oxide, etc.) is usually observed, and the key factor in this process is the activation of the signal transduction of cells, and signal proteins seem to be therapeutic targets for reducing the levels of pro-inflammatory response, so create products for the treatment of inflammation should have immune-modulatory activity. Thus, anti-inflammatory drugs of new generation should possess, if possible, antioxidant activity in order to neutralize oxidative stress, and immune-protective activity to correct the immune status in the damaged tissues, so synergistically overlapping both endothelium-protective and immuno-modulatory effects.

One of the promising area of ​​creating drugs having endothelium-protective activity is antioxidant enzymes as a basis, because the effectiveness of these enzymes are in several orders of magnitude higher than the antioxidant activity of commonly used low molecular weight compounds. These antioxidant enzymes can be especially peroxiredoxins and superoxidedismutase, which have a wide spectrum of activity and can be very promising for use as a basic component of a powerful drug carrying endothelium-protective activity. As to immunomodulators, it can be used thymus hormones, including thymopentin and thymulin, or theirs homologs; indeed, it have been shown that thymus peptides in acute and chronic inflammation can regulate the activity of immune system cells, and reduce the toxic effects caused by bacterial endotoxin.

Thus, the combined use of chimeric proteins, antioxidants and thymic peptides homologous is promising in the treatment of acute and different stages of chronic inflammation.

This work was supported by the RFFI, project No 13-04-00537-а; and by the Program of Presidium of Russian Academy of Sciences “Molecular and Cellular Biology”.

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