Nucleotide Analogs in Medicine

DNA polymerases and/or nucleotide metabolism enzymes are the targets of "designer" drugs. Target enzymes include the following:

> Deoxypyrimidine kinase of herpesvirus - This viral enzyme readily phosphorylates the drugs 5-iododeoxyuridine, acycloguanosine (acyclovir), and ganciclovir. The viral DNA polymerase attempts, in turn, to incorporate them into DNA in place of the corresponding dNTP. All three of the triphosphates of these drugs interfere with DNA replication. Uninfected cells do not efficiently phosphorylate acyclovir and ganciclovir and they phosphorylate 5-iododeoxyuridine only weakly, so DNA replication and virus growth are inhibited selectively in infected cells.

> DNA polymerases - Arabinosyladenine (araA) and arabinosylcytosine (araC) are readily converted to triphosphates (araATP and araCTP). AraATP is a selective inhibitor of the DNA polymerases of herpesvirus. araC is used in chemotherapy and functions by the same mechanism of inhibition on the cellular polymerase.

> Reverse Transcriptase - 3'-Azido-2'3'-dideoxythymidine (AZT), when converted to the corresonding 5' triphosphate in cells, is an inhibitor of the HIV reverse transcriptase enzyme, which is responsible for making viral DNA from viral RNA. Other nucleoside analogs, such as 2'3'-dideoxycytidine (ddC), 2'3'-dideoxyinosine (ddI), and 2'3'-didehydro-3'-deoxythymidine (d4T) (see here) are also converted to triphosphates and act by blocking DNA chain elongation after they are incorporated into DNA.

> Purine salvage enzymes - The drugs allopurinol (see here) and formycin B inhibit the action of cellular purine salvage enzymes. Thus, these drugs can be used to treat individuals infected by the parasitic protozans, Plasmodium, and Leishmania because these parasites lack the capacity for de novo purine synthesis (i.e., they depend entirely upon cellular purine salvage enzymes and bases provided by the host)

> Dihydrofolate reductase - Figure 22.18 illustrates the important role of dihydrofolate reductase in the pathways regenerating tetrahydrofolate from the dihydrofolate generated in the synthesis of dTMP from dUMP. Inhibitors of dihydrofolate reductase, such as methotrexate and trimethoprim, ultimately inhibit production of dTTP.

See also: Drug Design, Salvage Routes to Deoxyribonucleotide Synthesis, DNA Replication Overview (from Chapter 24), Eukaryotic DNA Polymerases (from Chapter 24), Retrovirus Replication (from Chapter 24)