An introduction to nucleoside and nucleotide analogues

The introduction of newer and more potent agents has diverted attention awa y from the importance of nucleoside analogue reverse transcriptase inhibito rs (NRTIs) in modern antiretroviral drug regimens. As a class, these provir al chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, d ue largely to their competitive mode of inhibition and requirement for meta bolic activation. However, neither NNRTIs nor Pis alone can maintain the co mplete suppression of HIV replication required for extended therapy, and bo th suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the mor e potent drug classes used with them. However, it has become apparent in re cent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safel y used. An independent contribution to peripheral fat Wasting in lipodystro phy syndrome has been established for the use of NRTI drugs. Of greater cli nical concern is their established association with potentially fatal lacti c acidaemia and hepatic steatosis. Both these class events, as well as seve ral individual drug events, such as peripheral neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of c onfidence. Mitochondrial toxicity, due in large part to the high affinity o f several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, gr eater efficacy in NRTI-experienced individuals, and greater long-term safet y. The nucleotide class of reverse transcriptase inhibitor (NtRTI), current ly under clinical development, addresses improved potency by abbreviating t he intracellular activation pathway to allow a more rapid and complete conv ersion to the active agent. These nucleoside monophosphate analogues are ta ken as masked prodrugs bearing labile lipophilic groups to facilitate penet ration of target cell membranes. Subsequent unmasking by endogenous chemoly tic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, c urrently in Phase III clinical trials. This agent has shown high potency an d an unusually durable response in trials of single-agent therapy intensifi cation in highly treatment-experienced individuals, and its active metaboli te, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for D NA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondr ial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF a nd other NtRTIs as 'second-generation' nucleoside analogues carefully evalu ated for potential long-term toxicity, can be expected to significantly imp rove the therapeutic options for both those currently on HAART and those ye t to begin.