Antiviral Activity of Uridine Derivatives of 2-Deoxy Sugars against Tick-Borne Encephalitis Virus

Abstract

Tick-borne encephalitis virus (TBEV) is a causative agent of tick-borne encephalitis (TBE), one of the most important human infections involving the central nervous system. Although effective vaccines are available on the market, they are recommended only in endemic areas. Despite many attempts, there are still no specific antiviral therapies for TBEV treatment. Previously, we synthesized a series of uridine derivatives of 2-deoxy sugars and proved that some compounds show antiviral activity against viruses from the Flaviviridae and Orthomyxoviridae families targeting the late steps of the N-glycosylation process, affecting the maturation of viral proteins. In this study, we evaluated a series of uridine derivatives of 2-deoxy sugars for their antiviral properties against two strains of the tick-borne encephalitis virus; the highly virulent TBEV strain Hypr and the less virulent strain Neudoerfl. Four compounds (2, 4, 10, and 11) showed significant anti-TBEV activity with IC50 values ranging from 1.4 to 10.2 µM and low cytotoxicity. The obtained results indicate that glycosylation inhibitors, which may interact with glycosylated membrane TBEV E and prM proteins, might be promising candidates for future antiviral therapies against TBEV.

Anti-Tick-Borne Encephalitis Virus Activity of Novel Uridine Glycoconjugates Containing Amide or/and 1,2,3-Triazole Moiety in the Linker Structure

“…As the initial steps of the biological evaluation of synthesized compounds we performed cytotoxicity studies according to the established method [ 19 ]. Cytotoxicity was analyzed using MTS-based cell proliferation assay in the permissive for TBEV—A549 cell line.…”

“…Preliminary screening of antiviral effects of eleven tested compounds was performed using two TBEV strains (Hypr and Neudoerfl) by assessing cytopathic effect (CPE) inhibition assay and plaque reduction assay as previously reported [ 19 ]. The compounds were tested at the non-toxic concentration of 25 µM.…”

“…As the first step of our research, we evaluated the antiviral activity of 11 novel uridine glycoconjugates containing amide or/and 1,2,3-triazole moiety in the linker structure against TBEV, a member of the Flavivirus genus. At the initial screening, four compounds (18,19,20,21) at the non-toxic dose (25 µM) significantly increased cell survival after infection of A549 cells with a pathogenic strain of TBEV (Hypr strain) (Figure 2). The antiviral activity of all glycoconjugates was further evaluated in the virus plaque formation assay, using a low pathogenic strain of TBEV (Neudoerfl strain) (Figure 3).…”

“…All of the uridine glycoconjugates showed dose-dependent cytotoxic effects with relatively moderate level of toxicity; below a concentration of 25 μM all of the compounds did not significantly influence the viability of the cells. Preliminary screening of antiviral effects of eleven tested compounds was performed using two TBEV strains (Hypr and Neudoerfl) by assessing cytopathic effect (CPE) inhibition assay and plaque reduction assay as previously reported [19]. The compounds were tested at the non-toxic concentration of 25 μM.…”

“…Inhibition of one of the GT with synthetic compounds may be a promising strategy for antiviral treatment for different flaviviruses. Previously, we have shown the antiviral activity of different uridine derivatives targeting GT against members of the Flaviviridae family—classical swine fever virus (CSFV), hepatitis C virus (HCV), and also against TBEV [ 18 , 19 , 20 ]. Moreover, the activity of these compounds was tested against influenza virus ( Orthomyxoviridae family member) [ 21 ].…”