Metabolism of Antiviral Nucleosides and Nucleotides

Abstract

Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy against human immunodeficiency virus (HIV), herpesviruses (including herpes simplex virus type 1 [HSV-1], HSV-2, varicella-zoster virus, and cytomegalovirus), and the hepatitis B and C viruses (HBV and HCV, respectively). Rather than providing a comprehensive discussion of the metabolism of individual agents, this chapter gives a general overview of enzymes involved in the metabolism of nucleoside and nucleotide analogs. It also highlights a few examples illustrating the unique pharmacology of the molecules. Competing with anabolism, various modes of catabolism and egress can serve to limit the maximal and temporal levels of the active species in target cells. Antiviral nucleoside and nucleotide analogs represent a large structural diversity with analogs mimicking virtually all the natural ribose and 2'-deoxyribose nucleosides and nucleotides. The importance of the 3' hydroxyl in the interaction of nucleosides with nucleoside transporters may differentiate the distribution of 3'-deoxynucleoside analogs and 3'-hydroxyl-containing nucleoside analogs. Anion and cation transporters with more general substrate specificity have also been identified to interact with nucleosides and nucleotides. In addition to anabolic drug interactions, highly catabolized nucleosides can have their levels altered due to interference with their degradation pathways. Drug interactions due to changes in elimination have also been observed to occur between nucleoside and nucleotide analogs and concomitant agents not related to nucleosides. Successful prodrug strategies promise to more effectively target infected tissues while decreasing exposure to sites of toxicity, offering the potential to increase efficacy while decreasing unwanted side effects.