title: Intracellular Metabolism of Nucleoside/Nucleotide Analogues: a Bottleneck to Reach Active Drugs on HIV Reverse Transcriptase.
abstract: BACKGROUND
  To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features.
  
  
  OBJECTIVE
  In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3'-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues.
  
  
  CONCLUSIONS
  Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, P.O. Box: 286, H-1519, Budapest, Hungary. matkovics.varga.andrea@ttk.mta.hu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Corinne
authors.initials: C
authors.lastname: Lionne
authors.forename: Béatrice
authors.initials: B
authors.lastname: Roy
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D009711:Nucleotides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase