Golovan A. Antiviral and apoptosis-inducing effect of heterocyclic compounds in the EBV-infection model

The thesis is devoted to the study of cytotoxic, antiviral and apoptosis-inducing action of heterocyclic compounds of nucleoside nature (compound №1 - 2- beta-D-rybofuranozyl-5-amino-1,2,4-triazine-3(2H)-on; compound №2 - 2-beta-D-rybofuranozyl-3(4H)-oxo-1,2,4-triazine[5,6-b][1,4]benzotiasine), the synthetic derivative of isonicotinic acid (compound №3 - 4-(N-benzyl)aminocarbonyl-1-metylpyridinium iodide) and herbal preparation Proteflazid (compound №4, active components are flavonoid glycosides heterocyclic) in Raji cells infected with Epstein-Barr virus (EBV) and B95-8 cell culture (virus producers). The model of acute EBV infection of Raji cells was created which had the optimal conditions for viral infections: active production of virus on the background of cell viability close to that in uninfected cells. It was found that low toxic test compounds for both cell lines had expressed antiEBV activity and effectively inhibited the virus replication under acute EBV-infection. Their high selectivity indexes (SI 280-2800) exceeded analogical indexes of the reference drugs acyclovir and ganciclovir. The compounds №1-3 were active against EBV under chronic EBV-infection (B95-8 cell culture). The compound №2 was the most effective in both types of EBV-infection. It was found that the compounds №1 and №4 induce the development of apoptotic cell death in both models of EBV-infection. The compound №3 modulates apoptosis under lytic EBV-infection of Raji and B95-8 cells that manifested in stimulating apoptosis and increasing the proportion of apoptotic cells compared with latent EBV-infection. For the first time the effect of test compounds on the expression of the antiapoptotic Bcl-2 cell protein were studied. It was found that the mechanism of realization of the apoptosis program induced by compound №3 under acute EBV-infection is associated with decreasing of the Bcl-2 protein.