An introduction to nucleoside and nucleotide analogues

• Published in: Antiviral therapy 2001-01, Vol.6 (3_suppl), p.1-14
• Main Author: SQUIRES, Kathleen E
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - adverse effects; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; HIV Infections - drug therapy; HIV-1 - drug effects; Humans; Medical sciences; Nucleosides - chemistry; Nucleotides - chemistry; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use
• ISSN: 1359-6535; 2040-2058
• DOI: 10.1177/135965350100603S01

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both 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 more potent drug classes used with them. However, it has become apparent in recent 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 safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of 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, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along