Biomedical subjects
Publications and source records attributed to A V Maksimenko.
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The mechanism of chemical ligation with cyanogen bromide in the presence of an N-substituted morpholine was studied. Addition of the cyano group to the tertiary nitrogen atom of the N-substituted morpholine with the formation of a quaternary ammonium cation is shown to be the first step of the reaction; it is this cation that activates the oligonucleotide phosphate group. This method of activation can be used to obtain phosphodiester derivatives of nucleotides without DNA duplex. Optimal conditions of the chemical ligation were selected.
Data on the content and localization of the recognition site (exosite) for high molecular weight substrates in the thrombin molecule have been summarized. It has been shown that this center, which binds anion sites of macromolecules, plays a key role in regulation of thrombin activity. Data of a proteolytic mechanism of platelet receptor activation by thrombin are reported. Prospects in biomedical studies of thrombin derivatives are discussed with the emphasis on developing new therapeutic tools and combined courses of thrombolytic therapy. Possibilities are discussed of developing a computer model of thrombin interactions for theoretical and applied purposes.
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Superoxide dismutase was covalently coupled wih aldehyde dextran, a polymeric carrier of molecular mass of 70 kDa. Modification produced an increase in the enzyme thermostability. Modified preparations retained a high specific activity. The composition of the thus obtained conjugates was analyzed by the ultracentrifugation and diffusion methods. The protein induced the destruction of aldehyde dextran, the enzyme being modified by its fragments. The presence of aldehyde dextran excess in the incubation medium promoted superoxide dismutase dissociation into individual subunits. At the enzyme/carrier ratio of 1:02 modification occurred as covalent coupling of the biocatalyst subunits and its one-point modification.
The present paper dwells on biomedical study of aldehyde dextran modified superoxide dismutase. Pharmacokinetic data demonstrated that modification of superoxide dismutase increased its half-time. A rat model of experimental silicosis showed that aldehyde dextran modified superoxide dismutase inhibited evolving fibrosis in the lungs. The same dose of native enzyme produced no therapeutic effect. Thus, superoxide dismutase can be considered as a potential agent for treatment of fibrosis due to its modification.
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Collagenase was gradually modified by aldehyde dextran and hyaluronidase. The modification increased enzyme stability and widened pH-optimum of its activity against specific and biological substrates. The modified complex with collagenolytic and hyaluronidase activity accumulated in the lungs of mice after intravenous injection. These results demonstrate its possible use for the treatment of lung disorders.
Urokinase was covalently bounded with modified thrombin. Thrombin was modified by carbodiimide and 1, 12-dodecamethylenediamine. In this conjugate thrombin is not catalytically active and does not induce platelets aggregation. The catalytic properties of modified urokinase do not essentially differ from native enzyme but its thermostability increases. The modified urokinase thrombolytic effect is at least 10-fold higher than the native one. In femoral arteries of experimental thrombosis the conjugate urokinase-thrombin brings about total thrombolytic effect as early as 1.5 hours after injection (2500 IU per 1 kg of the animals weight). The causes of the observed effect were discussed.
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Dextran-modified hyaluronidase was inhaled or intraperitoneally injected for 4 months to mice with silicosis. Stabilized hyaluronidase was shown to have a marked inhibitory effect on the development of lung fibrosis. Drug inhalation proved to be the most effective. An antifibrotic effect of dextran itself has been observed.
Successive thrombin modification by carbodiimide and aliphatic diamines decreases esterase and fibrin-coagulating activity of the enzyme. Modified thrombin causes no platelet aggregation. Water-soluble enzyme conjugates devoid of fibrinogen-coagulating action and possessing increased fibrinolytic affinity to the site of fibrin clot location have been obtained by covalent binding of chymotrypsin to modified thrombin.
Several approaches to development of systems for directed transport of drugs are illustrated by an example of thrombolytic therapy. Preparation and properties of enzyme derivatives with increased tropism to the thrombus material due to modification of enzymes by fibrinogen or specific antibodies are discussed. The data on directed transport of drugs under the action of the magnetic field and on the selective action of drugs on culture cells are also presented.
Modified hyaluronidase derivatives have been obtained. Covalent coupling of the enzyme with aldehyde dextran results in 65-85% protein binding to the carrier, residual catalytic activity accounting for 90-100% of the baseline. Modified hyaluronidase is more thermostable than the native enzyme. The data on intravenous drug distribution in the mouse organs are promising and ensure effective use of modified hyaluronidase for the treatment of pulmonary diseases.
The effect of salt concentration and its nature on some properties of alpha-chymotrypsin (the catalytic activity, the solution optical density, the sedimentation coefficient) has been considered. The limiting stage of enzyme-salt interaction has been shown to change with the variation of experimental conditions. As salt concentration increases the surface electrostatic interaction of salt ions with the enzyme molecule changes by ions penetration via certain channels within the protein globule and their subsequent binding to regulatory centers. The difference in ions nature and binding centers provides the variety of modifications observed. At high salt concentrations the solvent structure becomes predominant.