Design of Nucleoside Prodrugs for the Inhibition of Tick-Borne Encephalitis Virus Reproduction

The design of prodrugs for nucleoside antiviral agents is the primary approach to achieving target profiles not only in terms of safety but also efficacy. We have proposed a new chemotype of inhibitors of tick-borne encephalitis virus (TBEV) reproduction among N⁶-substituted adenosine derivatives, characterized by the presence of a hydrophobic aromatic substituent at the N⁶ position of adenine and benzoic acid residues attached via ester bonds to the ribofuranose scaffold. The compounds inhibited TBEV reproduction at micromolar concentrations only in their benzoylated form, while exhibiting no detectable cytotoxicity regardless of the substitution on the ribofuranose moiety. Our study demonstrates that modifying nucleoside analogs with hydrophobic groups can yield compounds with improved antiviral activity, and the identified compounds may subsequently serve as prototypes for the development of new antiviral drugs against epidemiologically significant pathogenic RNA viruses affecting humans.