The enantioselectivity of enzymes involved in current antiviral therapy using nucleoside analogues: a new strategy?

This review is primarily intended for synthetic bio-organic chemists and en zymologists who are interested in new strategies in the design of virus inh ibitors. It is an attempt to assess the importance of the enzymatic propert ies of L-nucleosides and their analogues, particularly those that are activ e against viruses such as human immunodeficiency virus (HIV), hepatitis B v irus (HBV), herpes simplex virus (HSV), etc. Only data obtained with purifi ed enzymes have been considered and discussed. The examined enzymes include nucleoside- or nucleotide-phosphorylating enzymes, catabolic enzymes, vira l target enzymes and cellular polymerases. The enantioselectivities of thes e enzymes were determined from existing data and are significant only when a sufficient number of enantiomeric pairs of substrates could be examined. The reported data emphasize the weak enantioselectivities of cellular or vi ral nucleoside kinases and some viral DNA polymerases. Thus, cellular deoxy cytidine kinase has a considerably relaxed enantioselectivity with respect to a large number of nucleosides or their analogues, and it occupies a stra tegic position in the intracellular activation of the compounds. Similarly, HIV-1 reverse transcriptase often has a relatively weak enantioselectivity and can be inhibited by the 5-triphosphates of a large series of L-nucleos ides and analogues. In contrast, degradation enzymes, such as adenosine or cytidine deaminases, generally demonstrate strict enantioselectivities favo uring D-enantiomers and are used by chemists in asymmetric syntheses. The w eak enantioselectivities of some enzymes involved in nucleoside metabolism are more or less pronounced, and one enantiomer or the other is favoured de pending on the substrate. This suggests that the low enantioselectivity is fortuitous and does not result from evolutionary pressure, since these enzy mes do not create or modify asymmetric centres in substrates. The combined enantioselectivities of the enzymes examined in this review strongly sugges t that the field of L-nucleosides and their analogues should be systematica lly explored in the search for new virus inhibitors.