An introduction to nucleoside and nucleotide analogues.

摘要: The introduction of newer and more potent agents has diverted attention away from the importance nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack virological potency either non-nucleoside inhibitor (NNRTI) or protease (PI) drugs, due largely to their competitive mode inhibition requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain complete suppression HIV replication required extended therapy, both suffer serious class cross-resistance on therapeutic failure. Thus, NRTIs will remain essential components highly active therapy (HAART) foreseeable future, contribution regimen's subsequent preservation classes used with them. it become apparent recent years that current exhibit duration-dependent adverse events as which may limit length time they be safely used. An independent peripheral fat wasting lipodystrophy syndrome been established use NRTI drugs. Of greater clinical concern is association potentially fatal lactic acidaemia hepatic steatosis. Both events, well several individual such peripheral; neuropathy, linked progressive mitochondrial destruction lesser degree confidence. Mitochondrial toxicity, large part high affinity uptake by DNA polymerase gamma, demonstrated vitro vivo. New chain-terminating are urgently needed address issues improved potency, efficacy NRTI-experienced individuals, long-term safety. nucleotide (NtRTI), currently under development, addresses abbreviating intracellular activation pathway allow rapid conversion agent. These monophosphate analogues taken masked prodrugs bearing labile lipophilic groups facilitate penetration target cell membranes. Subsequent unmasking endogenous chemolytic enzymes releases partially activated metabolite. NtRTI furthest along developmental process tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, Phase III trials. This agent shown unusually durable response trials single-agent intensification treatment-experienced its metabolite, diphosphate, exhibits long half-life resting blood mononuclear cells permits once daily dosing. Tenofovir diphosphate also very low gamma vitro, suggesting vivo toxicity observed follow-up, although data support this inference not yet available. TDF other NtRTIs 'second-generation' carefully evaluated potential expected significantly improve options those HAART begin.