Handbook of Experimental Pharmacology issue:189 pages:53-84
Nucleoside or nucleotide analogue inhibitors of viral replication almost act as chain terminators during DNA (DNA- and retroviruses) or RNA (RNA viruses) synthesis. Following intracellular phosphorylation, by viral and/or cellular kinases, the 5'-triphosphate metabolites (or 2'-diphosphate metabolites in the case of acyclic nucleoside phosphonate analogues) compete with the natural substrate in the DNA or RNA polymerization reaction. Obligatory chain terminators (e.g., acyclovir) do not offer the 3'-hydroxyl function at the riboside moiety of the molecule. Nucleoside analogues that possess a hydroxyl function at a position equivalent of the 3'-hydroxyl position may act as chain terminators if this hydroxyl group is conformationally constrained (e.g., ganciclovir) or sterically hindered to enter into a phosphodiester linkage with the incoming nucleotide. In case that the 3'-hydroxylgroup is correctly positioned, chain elongation may be hampered through steric hindrance from neighboring substituents (e.g., 2'-C-methyl or 4'-azido nucleoside inhibitors of HCV replication). Here, we review the molecular mechanism of action and the clinical applications of the nucleosides and nucleotides acting as chain terminators. A further discussion of clinical applications in combination therapy can be found in Chap. 12.