Date Published: , 2010
Publisher: A.I. Gordeyev
Author(s): A.V. Maksimenko, A.V. Vavaev, L.I. Bouryachkovskaya, V.P. Mokh, I.A. Uchitel, V.L. Lakomkin, V.I. Kapelko, E.G. Tischenko.
Bienzyme conjugate was obtained by the covalent connection of superoxide dismutase with catalase through endothelial glycocalyx glycosaminoglycan – chondroitin sulfate (SOD-CHS-CAT). This SOD-CHS-CAT conjugate has vasoprotective activity in respect to platelet interactions, tonus of the ring arterial fragment of a rat blood vessel, as well as normalization of hemodynamic parameters in rats and rabbits in conditions of oxidative stress caused by the administration of hydrogen peroxide. The SOD-CHS-CAT conjugate had antiplatelet potential due to its antiaggregation action manifested through the combination of enzyme activities and an acquired supramolecular structure. The influence on arterial fragment tonus was equivalent for SOD and CAT in native and conjugated form. Blood pressure and heart rate were significant and effectively normalized with SOD-CHS-CAT conjugate in rats and rabbits (after hydrogen peroxide administration as a perturbance stimulus). We have discovered the possibility of using the antioxidant bienzyme conjugate in chronic prophylaxis. It is important for a real development of the oral form of the SOD-CHS-CAT conjugate. These results indicate that the development of enzyme conjugates can be medically significant, as a promising approach for the creation of new drugs.
Enzymes are widely used as medication in thrombolytic therapy [1, 2]. The “golden molecule” of fibrinolysis and “golden time” of thrombolysis are known to increase the arsenal of biocatalysts used in treatment [3, 4]. However, the therapeutic applications of enzymes are far from having been exhausted, and there is a search for new forms that can be used in the development of original treatments for various pathologies [5, 6].
The effects of SOD-CHS-CAT on platelets
The results of the present study indicate that supra-molecular enzymatic conjugates are potentially effective and safe and that they can be used in practical medicine. Covalent cross-linking of enzymatic subunits accounts for a mutual stabilization of biocatalyst activity. Augmented molecular weight and the inclusion of chondroitin sulphate (glycosoaminoglycan of the endothelial glycocalyx) in the conjugate results in a vasoprotective activity of the SOD-CHS-CAT derivate on the inner surface of the vascular wall. The therapeutical effect of the SOD-CHS-CAT is determined by covalent coupling of SOD and CAT activities, which underlies their combined action and formation of harmless products of enzymatic conversion. The supra-molecular structure of the nanoconjugate accounts for its previously unknown quality – the capacity to prevent induced platelet aggregation. The activity of the components of the SOD-CHS-CAT conjugate is very pronounced, since the influence of the SOD and CAT activities of the conjugate on the tone of the vascular fragment is similar to that of native enzymes. The contribution of chondroitin sulphate to the antiaggregational effect is also very clear. The described qualities determine the higher antioxidant activity of the SOD-CHS-CAT conjugate, as compared to the other combinations of its individual components. The SOD-CHS-CAT conjugate is well-tolerated, it possesses satisfactorily acute toxicity, normalizing action in relation to hemodynamics under oxidative stress, and a pronounced therapeutical effect. All these factors make the conjugate a prospective drug candidate. This study represents a new approach to the development of therapeutically significant enzymatic conjugates.