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Since the approval of the first-in-class anti-HIV drug 3’-azido-3’-deoxythymidine (AZT), nucleoside and nucleotide analogues have gained much attention, even now, with new classes of antivirals found. This conservative therapy is the most affordable; currently used drugs offer such pharmaceutical benefits as good water solubility, inexpensive synthesis, thoroughly studied mechanisms of action and resistance. Nevertheless, 30 years on, the topic remains: to make nucleosides and nucleotides less toxic in the long-term treatment.