Current therapeutic strategies against HIV include nucleoside analogues, typically combined with protease inhibitors. Nucleoside analogues stop the spread of HIV by inhibiting the viral replicating enzyme, reverse transcriptase, but show little to no effectiveness in preventing replication once the virus has successfully integrated into the host cell chromosome. A nucleotide is composed of a five-carbon sugar, a nitrogenous base, and one phosphate group. A nucleoside is composed of a five-carbon sugar, and a nitrogenous base, with no phosphate group. Nucleosides therefore require three phosphorylation steps to become triphosphates, and therefore substrates for DNA synthesis.
Nucleotides only require two phosphorylations.
The nucleoside kinase responsible for the initial phosphorylation step is cell type and cell cycle specific, and its absence may limit the activation process of nucleosides. The enzymes responsible for the second and third phophorylation steps, required by both nucleosides and nucleotides, occur in a much wider range of cells. In this study, researchers tested Adefovir dipivoxil, a nucleotide analogue and a derivative of Adefovir, for its effectiveness against HIV and safety in humans. In a previous study, unmodified Adefovir was shown to have poor bioavailability due to the negative charges of the phosphate group which caused decreased intestinal absorption. To control this problem, the drug was altered to an ester form, Adefovir dipivoxil.