The molecular-biological special features of the action of Arbidol the new antiviral preparation

 

No. 12 | 2002

 

Arbidol, the new antiviral preparation, effective with respect to the viruses of influenza A and B. the Molecular- biological special features of the action of Arbidol are determined by its ability to suppress the reproduction of virus at the early stages, the action of preparation realizes with a change in the regulation of cellular metabolism. Preparation is differed from remantadine in the molecular mechanism of antiviral action.

 

Arbidol of 1-methyl-2-feniltiometil-3-karbo3ndoksi-4-dimetilaminometil-5- hydroxy -6-bromindola, hydrochloride, monohydrate, (C22H25BrN2OS(.HCl(H2O) the antiviral preparation, created in TSKHLS OF VNIKHFI - ALL-UNION SCIENTIFIC RESEARCH CHEMICAL AND PHARMACEUTICAL INSTITUTE IM. SERGO ORDZHONIKIDZE.

 

In the present work are cited the data about the molecular mechanism of the antiviral action of Arbidol. As is known, the mechanism of the reproduction of the virus of influenza is unique, since the specific cooperation of virus and cellular factors is provided for.

 

By the method VEZHKH it is shown that Arbidol penetrates in the unchanged form both into that not contaminated and the infected cells and is determined in the nuclear and in the cytoplasmic fractions.

 

The revealed localization of Arbidol in the cell nucleus is connected with the action of preparation on one of the stages of the synthesis of cellular and virus-specific macromolecules.

 

The disrupted synthesis of cellular macromolecules is reversed and rapidly it is restored with the termination of the action of preparation. It is shown that the oppression of synthesis DNA occurs after only 15 minutes after its introduction, reaching maximum to 30 minutes. Synthesis RNA is inhibited more slowly, effect increases during 24 it is hour.

 

Arbidol does not form complex with DNA and does not manifest the intercalating properties.

 

Under the effect of Arbidol occurs the induction of the production of interferon in the culture of cells FEK, in the blood serum of mice, which is compared with the activity of the preparation ds- RNA of phage RF2.

 

The use of the flyuorestsentnomechennogo virus made it possible to study the influence of Arbidol in the comparison with remantadine on these processes. In the presence of Arbidol (50 g/ml) with pH 5.0 is observed the significant inhibition of the coloring of flyuorestsenzii (RF). The same inhibition RF with pH 5.0 occurs in the presence of remantadine (25 g/ml).

 

Addition to the reaction medium of Arbidol in the concentration 50 g/ml with pH 7.4 also caused the decrease OF RF. Remantadine in the concentrations 25-1000 g/ml did not render the suppressing action on RF.

 

Obtained data make it possible to make the conclusion that Arbidol inhibits the confluence of the lipid shell of virus with the plasmatic membranes of cell, proceeding outside and induced by the low level pH 5.0, and also the confluence of the lipid shell of virus with the membranes endosome, proceeding inside the cells under the physiological conditions with pH 7.4. Remantadine, in contrast to Arbidol, inhibits only the confluence of the lipid shell of virus with the plasmatic membranes of cells, without acting on the confluence of the lipid shell of virus with the membranes endosome.

 

It is widely acknowledged that under the physiological conditions in the cells with the reproduction of the virus of influenza the liberation of nucleocapsid occurs inside endosome. Literature data the obtained results make it possible to assume that the virusingibiruyushchiy effect of Arbidol is connected with the stage of the reproduction of virus with the confluence of the lipid shell of virus with the membranes endosome, proceeding inside the cells with pH 7,4. Therefore by us was studied the influence of different concentrations of Arbidol on this process. The obtained results show that the inhibition of value RF began with the concentration of Arbidol 5 g/ml (8%) and increased with the concentration of Arbidol to 50 g/ml. With the concentration of preparation of above 50 g/ml the inhibition RF did not change and composed 60%. It is important to emphasize that these results coincide with the data of the virusological of the studies, in which minimum inhibition BO (blyashkoobrazovaniye) and TSPD (cytopathic action) in the cellular culture was observed with the concentrations of Arbidol 5-10 g/ml.

 

The analysis of represented data shows that one of the vulnerable stages of the reproduction of the virus of influenza under the effect of Arbidol is the confluence of the lipid shell of virus with the membranes endosome, proceeding inside the cells under the physiological conditions during the release of the genetic material of virus from the external proteins and the lipid shell. In contrast to amantadine and remantadine, Arbidol inhibits release of nuklekapsida itself from the external proteins, neuraminidases (NA) and lipid shell.

 

It is shown that Arbidol influences the process of merging the lipid shell of virus with the plasmatic membrane with pH 5.0, which can be caused by the incorporation of preparation into the lipid membranes and by influence on the conformational changes NA. There is no doubt that the designation of antiviral preparation at the early stages of virus reproduction is most effective, since in the cells the irreversible cytopathic changes yet did not occur.

Literature

Bubovich V.I., Ryazantseva G.M., Indulem M.K. the early stages of the multiplication of microes-virus and the influence on them of inhibitors. Riga, 1987.

Virology/edited by Fields V., Nayd d. M., 1989, Vol. 2.

Gerasina s. f., Parashchyan EXPLOSIVE, Fadeyev N. i./pharmacology and toxicology, 1985, №ya, s. 92-95.

Tupitsin D.L., Severin NUMBER SYSTEMS/Of biokhimi, 1983, Vol. 50, iss. 4, s. 531-532.

Kozeletskaya K.L., Dubrovin T.ya., Mishcheryakova i. e. and other virus inhibitors and the mechanisms of their action. Riga, 1977, s. 55- 67.

Laneva I. A., Gulak P.V., Dubrov- Sobolyev A.S./the Experimental Biology Bulletin, 1990, №ya, s. 483-485.

Fadeyev N.I., Permagorov V. i., Sokolov N.D. and other/Chem.- pharm periodical, 1987, №y, s. 5-7.

Clerok E De Recent Advances In the Research For Selective Antiviral Agents./London, Boston, Toronto, 1988.

Belshe R, Hay A J resp. Dis., 1989, Suppl., p 852-861.

Bound G E, Sommervill R.G. Arch. Virusfosch, 1974, p. 78-85.

Kerr I M, Brown R.E./Proc. nat. Acad. Sci. USA, 1978, vol. 75, r. 256-260.