NUCLEOSIDE ANALOGS - SIMILARITIES AND DIFFERENCES

Among the steps in the replication cycle of human immunodeficiency virus (HIV) that are potential targets for antiviral chemotherapy, the viral DNA polymerase or reverse transcriptase has been a target of choice in research on anti-HIV drugs. Nucleoside analogs-the agents studied in relation to this target-have no intrinsic activity against HIV and must be metabolized to their respective 5'-triphosphates by means of kinases, nucleotidases, or other activating enzymes present naturally in cells. The presence and activity of the intracellular enzymes necessary for activation of nucleoside analogs are highly dependent on host species, cell type, and stage in the cell cycle. A great advantage of 2',3'-dideoxynucleosides is their intracellular pharmacokinetic profile. The multifactorial mechanisms of toxicity associated with this class of drugs likely explain the different spectra of toxicity observed with the various individual nucleoside analogs and exemplify the uniqueness of each compound. Recently, strains of HIV resistant to 3'-azido-3'-deoxythymidine (zidovudine) were isolated from patients who had been treated with this drug; this resistance probably reflects sequential acquisition of amino acid mutations in the HIV reverse transcriptase.