Structural features of nucleosides as antiviral agents

Nucleoside analogs as inhibitors of viral replications usually act by interaction of their triphosphates with viral polymerases. As structural units of nucleic acids, the nucleoside triphosphates (NTPs) are the substrates for polymerase enzymes, which catalyze the polymerization of the NTPs. The biosynthesis of the NTPs is controlled by nucleoside kinases. The structural requirements of nucleosides to interact with kinases and polymerases have important implications in the design of potential antiviral nucleosides (Figure 1). The 5'-hydroxymethyl group and the base moiety of nucleosides interact with kinases and their complementary nucleotides on the DNA template. The sugar moiety of the nucleoside can be considered as a spacer to connect the hydroxymethyl group and the base moiety.6 Therefore, modification of the sugar moiety has provided opportunities in the design of biologically active nucleosides.

Some viruses, such as herpes viruses, encode their own nucleoside-phosphorylat-ing enzymes, which offers the potential for a therapeutic target.6 Nucleosides, which are preferably phosphorylated by viral enzymes rather than by the cellular homologue, are only activated in infected cells and can have high selectivity against these viruses. This is, for example, the main factor in the success of acyclovir (ACV). However, other viruses, such as HIV and HBV, do not encode nucleoside kinases. In order to be active against these viruses, nucleoside analogs have to be phosphorylated by cellular kinases. Thus, the selectivity between antiviral activity and cellular toxicity depends on the substrate specificity of the NTPs for viral and host polymerases, and often the therapeutic exploitation of active nucleosides is compromised by the toxicity resulting from inhibition of the host enzymes or incorporation in the host nucleic acids.

In general, enzymes act on one enantiomer of a chiral substrate, the specificity of which is related to the unique structure of the enzymes.7 However, recent findings have indicated that there are some exceptions to this rule among enzymes involved in the phosphorylation of nucleosides.7'8910 For instance, herpes virus thymidine kinases (TKs) phos-phorylate both d- and l-enantiomeric forms of several uracil analogs as well as acyclic nucleosides, cellular deoxycytidine (dCyd) kinase phosphorylates both enantiomeric forms of several dCyd analogs, and some viral DNA polymerases, such as herpes viruses, HIV-1 RT and HBV DNA polymerase, are inhibited by the triphosphates of a number of l-nucleosides. These findings offer new opportunities for antiviral chemotherapy, although, at the molecular level, it is not completely understood how kinases phosphory-late both d- and l-nucleosides.

In recent years, a growing number of nucleoside analogs have been discovered which exert their antiviral activity by inhibiting enzymes different from polymerases, such as inosine monophosphate dehydrogenase, S-adenosylhomocysteine hydrolase, orotidine 5'-monophosphate decarboxylase and CTP synthetase.11 Such compounds may prove useful because, by targeting different enzymes, they may offer synergistic action with classic polymerase inhibitors.

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