Role of Nucleotide Analogs as Cytotoxic and Antiviral Drugs

DNA in the chromosomes is normally protected by active repair systems against damage by a variety of chemical and physical agents, including ionizing radiation and ultraviolet light. Proofreading activities guard against the incorporation of mismatched nucleotides during DNA replication or transcription. In contrast, the use of certain nucleotide analogs as drugs depends on their incorporation into DNA— the chemical must be recognized and used by the replication enzymes but must prohibit further elongation of the nucleic acid chain. Analogs used in HIV therapy are incorporated by the reverse tran-scriptase of the virus and bring the reaction to a halt. Toxicity associated with several analogs is known to arise from erroneous incorporation into the patient's mitochondrial DNA because of less stringent proofreading by the mitochondrial DNA polymerase enzyme. Azidothymidine remains one of the most effective and least toxic drugs for AIDS, albeit it is now usually taken in triple therapy.

Nucleotide analogs have been used to inhibit the de novo pathways for the synthesis of the precursor nucleosides and nucleotides, leading to depletion of metabolites and imbalance of dNTPs, and hence to misincorporation of nucleotides in RNA or DNA, respectively. Malaria and other parasites rely exclusively on de novo pyrimidine biosynthesis; thus, they may be susceptible at drug doses that do not affect the host because the human body can obtain nucleo-tides from the salvage pathway. Similarly, because of the increased requirement for nucleotides in rapidly proliferating cells, almost all the enzyme reactions (Figure 2) have been investigated as potential targets for treatment of cancer, inflammation, or to prevent rejection of transplanted organs. Again, combinations of drugs with different modes of action have often proved most effective.

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