Antiviral nucleoside and
nucleotide analogs, essential for the treatment of
viral infections in the absence of efficient
vaccines, are
prodrug forms of the active compounds that target the
viral DNA polymerase or
reverse transcriptase. The activation process requires several successive phosphorylation steps catalyzed by different
kinases, which are present in the host cell or encoded by some of the viruses. These activation reactions often are rate-limiting steps and are thus open to improvement. We review here the structural and enzymatic properties of the
enzymes that carry out the activation of analogs used in
therapy against human immunodeficiency virus and against DNA viruses such as
hepatitis B, herpes and poxviruses. Four major classes of drugs are considered:
thymidine analogs, non-natural L-
nucleosides, acyclic
nucleoside analogs and acyclic
nucleoside phosphonate analogs. Their efficiency as drugs depends both on the low specificity of the viral polymerase that allows their incorporation into
DNA, but also on the ability of human/viral
kinases to provide the activated
triphosphate active forms at a high concentration at the right place. Two distinct modes of action are considered, depending on the origin of the
kinase (human or viral). If the human
kinases are house-keeping
enzymes that belong to the metabolic salvage pathway, herpes and poxviruses encode for related
enzymes. The structures, substrate specificities and catalytic properties of each of these
kinases are discussed in relation to drug activation.