ENZYMATIC SYNTHESIS OF NUCLEOSIDE ANALOGUES OF 1,2,4- TRIAZOLE AND THEIR ANTIVIRAL ACTIVITY
Abstract
Nucleoside analogues (or modified nucleosides) are heterocyclic nitrogenous bases of natural or synthetic origin, structurally similar to naturally occurring nucleosides, containing cyclic pentoses -ribose, deoxyribose and arabinose.Modified nucleosidesare used as antiviral, anticancer and antibacterial drugs [1][2][3].Recently, the role of nucleoside analogues of 1,2,4triazole as antiviral agents has increased.Synthesis ofsuch compounds is possible either by methods of chemical synthesis or with biocatalysis.A long multi-stage chemical synthesis has a number of significant drawbacks."One-pot" enzymatic reactions using recombinant nucleoside phosphorylases (NP) provide an alternative way of making some nucleoside analogues and has proved to be highly effective [4].NP catalyzes the reversible phosphorolysis of ribo-or 2'deoxyribonucleosides to form a free heterocyclic base and ribose or 2-deoxyribose-1-phosphate (transglycosylation reaction).In this work, we studied the substrate specificity of recombinant E. coli purine nucleoside phosphorylase (EcPNP) to 3,5-substituted-1,2,4-triazoles and evaluated the antiviral effect of the obtained nucleosides on two strains of Herpes simplex virus type-1 (HSV-1), including a strain resistant to the antiherpetic drug acyclovir.The main result of study was that for the first time the new 3,5-alkyl/aryl-substituted-1,2,4triazole nucleosides have been synthesized using enzymatic transglycosylation.The surprising ability of EcPNP to synthesize ribo-and 2-deoxyribonucleosides having structurally diverse hydrophobic substituents at the 3 and 5 position of 1,2,4-triazole has been discovered.3,5-Alkylsubstituted-1,2,4-triazole nucleosides showed remarkable anti-herpes viral effect, which is expressed in the inhibition of the development of a virus-induced cytopathic effect in a culture of Vero E6 cells infected with various strains of HSV-1.