Practical considerations for developing nucleoside reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors (NRTI) remain a cornerstone of current antiretroviral regimens in combinations usually with a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor (INI). The antiretroviral efficacy and relative safety of current NRTI results from a tight and relatively specific binding of their phosphorylated nucleoside triphosphates (NRTI-TP) with the HIV-1 reverse transcriptase (RT), which is essential for replication. The intracellular stability of NRTI-TP produces a sustained antiviral response, which makes convenient dosing feasible. Lessons learned regarding NRTI pharmacology screening, development and use are discussed. NRTI and prodrugs currently under clinical development are outlined.