The dissertation is related to the research of the properties and mechanisms of antiviral action of fluoride-containing nucleosides, amino acid derivatives, nanoparticles and natural substances that belong to plant flavonoids. The studies were performed on the model of adenovirus infection induced by serotypes 3, 5, and 7.
We analyzed the effect of newly synthesized fluoride-containing compounds on the epithelial cell line and analyzed their anti-adenoviral potential. It was found that the determined values of the cytotoxicity correlated with their solubility and structural properties. It was identified that only highly soluble compounds (G26, G27, 10S-23,10S-24) possessed low toxicity for cells, while the CC50 values for these substances started from 630 and significantly exceeded the value of 1000 mcg/ml. Compounds G22 and G23 with the CC50 values of 250 and 125 mcg/ml, respectively, were more toxic for cells. It was shown that the triazole-derived compounds (G22, G26, and G29) and derivatives of amino acids (10S-23) effectively suppressed the reproduction of adenovirus serotype 5. Compounds G22, G26 and 10S-23 significantly inhibited the cytopathogenic effect of the virus and the formation of virus-specific inclusions (up to 62 %). Compounds G26 and 10S-23 suppressed the replication of viral DNA by 27 – 100 %. Effective antiviral concentration (EC50) for compounds G22, G26, G29 and 10S-23 equaled 60, 120, 37 and 90 mcg/ml, whereas the chemotherapeutic indexes were 4, 5, 13, and 11, respectively. Moreover, it was found that compound G29 (2-(3-clorotetrahydrofuran-2-yl)-4-tosyl-5-(perfluoropropyl)-1,2,3-triazole) normalized the cell cycle of the infected cells to the level of non-infected cells and reduced the infectious titer of adenovirus by 84 – 90 %.
We studied the effect of gold nanoparticles, gold-silicon nanoparticles and titanium dioxide nanoparticles on the model of adenovirus infection. It was shown that all types of analyzed nanoparticles had high CC50 values demonstrating that their toxic effect did not exceed 10 %. It was found that the mentioned authorial nanoparticles possess virucidal action and photocatalytic properties (titanium dioxide nanoparticles). Type “a” silicon-based nanoparticles demonstrated significant inhibitory potential on the reproduction of adenovirus serotype 5. The level of virus inhibition ranged between 55 and 96 %. Type “b” silicon nanoparticles at the concentrations between 10-2 and 10-4 suppressed the reproduction of adenovirus by 100 %. These particles also showed virucidal action against HAdV-5 (2 h exposition of the virus with nanoparticles was the most efficient due to the stable virucidal effect, 66 – 86 %). It was shown that gold nanoparticles of 5 and 20 nm in size effectively reduced the level of adenovirus reproduction by 100 %. It was also found that these nanoparticles have virucidal activity against adenovirus serotype 5 (39 – 42 %). Gold nanoparticles with a diameter of 5 nm and 20 nm minimized the virus titer by 2 orders.
Antiviral activity of TiO2 nanoparticles (II) against human adenovirus serotype 5 ranged between 45 – 95 %. It was found that these nanoparticles possessed photocatalytic properties that suppressed adenovirus by 30 %. We demonstrated that titanium dioxide nanoparticles possessed virucidal action against adenovirus serotype 5. The sample of TiO2 (I) showed significant suppression of virus reproduction by 49 %, whereas TiO2 (II) inhibited the reproduction by 63 %.
We identified antiadenoviral activity of the drug Neoflazid, obtained from plant flavonoids, using a model of adenovirus serotype 5. It was found that the antiviral properties of the drug are based on the direct effect on the de novo formation of viral progeny. We showed that Neoflazid, BAS (biologically active substance extracted from the drug) and BAS SA (a synthetic analogue of the biologically active substance extracted from the drug) at concentrations 7.1 mcg/ml, 30 mcg/ml and 10 mcg/ml, respectively, suppressed the formation of infectious adenovirus synthesized de novo by 100 %. It was identified that Neoflazid and its active components BAS and BAS SA did not have virucidal activity against adenovirus serotype 5. Although Neoflazid, BAS and BAS SA did not show obvious anti-adenoviral activity, they efficiently suppressed the synthesis of new viral progeny (by 97 – 100 %).
For the first time, we studied the cytotoxic and antiviral activity of Plantago and raspberry extracts on the models of adenovirus serotypes 3, 5, and 7. Only raspberry extract showed affected the reproduction of all studied serotypes. The value of the inhibition of viral infection ranged between 45 and 100 %. It was found that the plant extracts also affected de novo synthesis of adenovirus. The most significant decrease in titer was identified for adenovirus serotype 5. The raspberry extract decreased the titer of this serotype by two orders (from 1.45 lg to 1.6 lg).
