Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine

doi:10.1016/j.antiviral.2009.09.014

Antiviral Research

Volume 85, Issue 1, January 2010, Pages 39-58

https://doi.org/10.1016/j.antiviral.2009.09.014 Get rights and content

Abstract

Twenty-five years ago, nucleoside analog 3′-azidothymidine (AZT) was shown to efficiently block the replication of HIV in cell culture. Subsequent studies demonstrated that AZT acts via the selective inhibition of HIV reverse transcriptase (RT) by its triphosphate metabolite. These discoveries have established the first class of antiretroviral agents: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs). Over the years that followed, NRTIs evolved into the main component of antiretroviral drug combinations that are now used for the treatment of all populations of HIV infected patients. A total of thirteen NRTI drug products are now available for clinical application: eight individual NRTIs, four fixed-dose combinations of two or three NRTIs, and one complete fixed-dose regimen containing two NRTIs and one non-nucleoside RT inhibitor. Multiple NRTIs or their prodrugs are in various stages of clinical development and new potent NRTIs are still being identified through drug discovery efforts. This article will review basic principles of the in vitro and in vivo pharmacology of NRTIs, discuss their clinical use including limitations associated with long-term NRTI therapy, and describe newly identified NRTIs with promising pharmacological profiles highlighting those in the development pipeline.

This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010.

Introduction

In 1985, two years after the identification of human immunodeficiency virus (HIV) (Barre-Sinoussi et al., 1983) and one year after the initial evidence about its etiological link to AIDS was reported (Gallo et al., 1984), Mitsuya et al. (1985) in Samuel Broder's group at the National Cancer Institute together with collaborators from Burroughs-Welcome company identified 3′-azidothymidine (AZT, zidovudine) as the first nucleoside inhibitor with in vitro anti-HIV activity. As described by Samuel Broder in the introductory chapter of this issue of Antiviral Research (Broder, 2010), the discovery of the anti-HIV activity of AZT was a defining moment, providing the first proof of concept that the replication of HIV could be controlled by chemotherapy and thereby establishing the foundation of antiretroviral drug discovery research. Furman et al. (1986) from Burroughs-Welcome first showed that AZT acts through its triphosphate metabolite by inhibiting reverse transcriptase (RT), the key enzyme of HIV responsible for the synthesis of proviral DNA. Thus, AZT became the first nucleoside HIV reverse transcriptase inhibitor (NRTI). Over the course of 25 years that followed after this seminal discovery, seven nucleosides and one nucleotide have been approved by the United States Food and Drug Administration for the treatment of HIV infection starting with the approval of AZT in 1987 and followed by didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), tenofovir disoproxil fumarate [TDF; prodrug for the oral delivery of the nucleotide analog tenofovir (TFV)] and, most recently in 2003, emtricitabine (FTC). A historical perspective on the discovery and development of the first generation NRTIs that became available in clinic within few years after the approval of zidovudine and played crucial role in the management of HIV/AIDS patients especially during the first decade of antiretroviral therapy is presented elsewhere in this issue (Martin et al., 2010).

Like in the case of other antiviral therapies such as those against herpes and hepatitis B viruses, nucleoside and nucleotide analogs have become the cornerstone of successful treatment of HIV infection. The goal of this review is to summarize basic principles of the in vitro and in vivo pharmacology of NRTIs together with their current role in HIV therapy including some of the main challenges associated with their long-term clinical application. Together with profiles of inhibitors that are currently in development as well as some recently identified NRTIs and their prodrugs, this article will also discuss prospects and potential roles of NRTIs in future antiretroviral therapy.

Section snippets

Molecular pharmacology of NRTIs

NRTIs are analogs of endogenous 2′-deoxy-nucleosides and -nucleotides. They are inactive in their parent forms and require successive phosphorylation steps by host cell kinases and phosphotransferases to form deoxynucleoside triphosphate (dNTP) analogs capable of viral inhibition. In their respective triphosphate (TP) forms, NRTIs compete with their corresponding endogenous dNTPs for incorporation by HIV RT. Once incorporated, they serve as chain-terminators of viral reverse transcripts, thus,

Current role of NRTIs in HIV therapy

NRTIs are the backbone of current combination antiretroviral therapy. The standard of care for HIV patients, referred to as highly active antiretroviral therapy (HAART), consists of three or more HIV drugs, most commonly two NRTIs in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor or, most recently, integrase inhibitor. The common use of combinations of NRTIs and the potential for reduced pill burden and increased adherence has led to the clinical

Limitations of approved NRTIs

While the unique pharmacology of NRTIs has helped them become the cornerstone of successful HAART, the effectiveness of NRTIs can be limited by drug–drug interactions, emergence of drug resistance, and adverse events. As there are more complete discussions of drug–drug interactions (Dickinson et al., 2010), antiretroviral resistance (Menendez-Arias, 2010), and adverse events of antiretroviral therapy (Hawkins, 2010) found elsewhere in this issue of Antiviral Research, we will focus on various

NRTI development pipeline

As discussed in the above sections, most of the currently used NRTIs have some safety and/or pharmacological limitations affecting their successful long-term use for the treatment of HIV-infected patients, either in general or in certain specific populations such as individuals genetically or medically predisposed to NRTI-related adverse effects, or those with NRTI resistance. Currently, there are multiple NRTIs in various stages of clinical development (Fig. 4). As discussed in the section

Novel NRTIs and their profiles

Although the total number of approved NRTI-based drug products together with compounds currently in clinical development exceeds twenty, the design and profiling of new NRTIs remains an active area of research, yielding a wide variety of novel HIV inhibitors with interesting profiles. In this section, three examples of structurally diverse classes of nucleosides will be reviewed (Fig. 5) followed by an update on the design of novel nucleoside phosphonates and their prodrugs (Fig. 6), all with

Future roles of NRTIs in the management of HIV infection

The contribution of NRTIs to highly effective long-term HIV suppression is at least in part due to their synergistic effects in combination with other classes of antiretrovirals. In addition, intracellular accumulation and prolonged retention of active metabolites of some NRTIs allows for their once daily dosing, is more forgiving towards non-adherence, and can buffer the pharmacokinetic fluctuations in levels of other drugs in any given regimen. Because of these unique properties, NRTIs are

Conclusion after 25 years of NRTIs: solid answers, yet many questions

There is no doubt that over the quarter of a century following the discovery of AZT as the first potent inhibitor of HIV, NRTIs have evolved into the cornerstone of effective antiretroviral therapy. When Mitsuya et al. (1985) were writing their first communication on the activity of AZT, they could hardly have envisioned the expansion and utilization of this class of drugs as we know it today. Since 1985, countless numbers of structurally diverse nucleoside and nucleotide analogs, as well as

Acknowledgement

We would like to thank Eric Lansdon of Gilead Sciences for the preparation of Fig. 3.

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ReviewNucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine

Abstract

Introduction

Section snippets

Molecular pharmacology of NRTIs

Current role of NRTIs in HIV therapy

Limitations of approved NRTIs

NRTI development pipeline

Novel NRTIs and their profiles

Future roles of NRTIs in the management of HIV infection

Conclusion after 25 years of NRTIs: solid answers, yet many questions

Acknowledgement

Biochem. Pharmacol.

Pharmacol. Ther.

J. Biol. Chem.

Antiviral Res.

J. Biol. Chem.

Biochem. Pharmacol.

Antiviral Res.

Antiviral Res.

Antiviral Res.

Biochem. Pharmacol.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Antiviral Res.

Antiviral Res.

Pharmacokinetic interaction between tenofovir and atazanavir coadministration with ritonavir in healthy subjects

Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals

AIDS

Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase

Biochemistry

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis

J. Acquir. Immune Defic. Syndr.

Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys

Antimicrob. Agents Chemother.

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives

Pharm. World Sci.

2′,3′-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis

Mol. Pharmacol.

Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates

Antimicrob. Agents Chemother.

Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS)

Science

In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (−)-beta-D-dioxolane-guanosine and suppress resistance to 3′-azido-3′-deoxythymidine

Antimicrob. Agents Chemother.

Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients

AIDS

In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs

Antiviral Chem. Chemother.

In vitro interactions between apricitabine and other deoxycytidine analogues

Antimicrob. Agents Chemother.

Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors

Antimicrob. Agents Chemother.

Multidrug resistance-associated proteins 3, 4, and 5

Pflugers Arch.

Predictive value of treatment effects in SIV/SHIV infections in monkeys

Curr. Opin. Anti-Infect. Investig. Drugs

Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway

AIDS

Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects

J. Acquir. Immune Defic. Syndr.

Pharmacokinetic interaction between rifampin and zidovudine

Antimicrob. Agents Chemother.

Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients

AIDS

A phase I study to explore the safety, tolerability, and pharmacokinetics of Fosalvudine Tidoxil in patients infected with HIV-1

A phase-II study of 14 days monotherapy with the nucleoside-analogue fosalvudine tidoxil in treatment-naïve HIV-1 infected adults

Racivir demonstrates safety and efficacy in patients harboring HIV with the M184V mutation and <3 TAM

48-week data from study AVX-201—a randomised phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance

J. Int. AIDS Soc.

Combination antiretroviral therapy without a nucleoside reverse transcriptase inhibitor: experience from 334 patients in three cohorts

HIV Med.

A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome

AIDS

Nucleoside transporters of mammalian cells

Pharm. Biotechnol.

The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients

HIV Clin. Trials

Anti-HIV activity of (−)-(2R,4R)-1- (2-hydroxymethyl-1,3-dioxolan-4-yl)-thymine against drug-resistant HIV-1 mutants and studies of its molecular mechanism

J. Med. Chem.

Review
Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine