text: Activation of nucleoside and nucleotide reverse-transcriptase inhibitors is primarily dependent on cellular entry by passive diffusion or carrier-mediated transport. NRTIs are highly hydrophilic and have limited membrane permeability and therefore this step is very important.
  NRTIs are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. They are inactive in their parent forms and require successive phosphorylation.
  Nucleosides must be triphosphorylated, while nucleotides, which possess one phosphonated group, must be diphosphorylated. This stepwise activation process occurs inside the cell and is mediated by a coordinated series of enzymes. The first, and often rate limiting, phosphorylation step (for nucleoside analogues) are most commonly catalyzed by deoxynucleoside kinases. Addition of the second phosphate group to nucleoside monophosphate analogues is completed by the nucleoside monophosphate kinases (NMP kinases). A variety of enzymes are able to catalyze the final phosphorylation step for NRTIs, including nucleoside diphosphate kinase (NDP kinase), phosphoglycerate kinase, pyruvate kinase and creatine kinase, resulting in formation of respective antivirally active triphosphate analogues.
  In their respective triphosphate forms, NRTIs and the only NtRTI available compete with their corresponding endogenous deoxynucleotide triphosphate (dNTPs) for incorporation into the nascent DNA chain (see figure 1). Unlike dNTPs substrate, NRTIs lack a 3´-hydroxyl group on the deoxyribose moiety. Once incorporated into the DNA chain, the absence of a 3´-hydroxyl group, which normally forms the 5´- to 3´- phosphoester bond with the next nucleic acid, blocks further extension of the DNA by RT, and they act as chain terminators.