Development of novel nucleoside analogues for use against drug resistant strains of HIV-1

doi:10.1016/S1359-6446(00)01558-0

Drug Discovery Today

Volume 5, Issue 10, 1 October 2000, Pages 465-476

https://doi.org/10.1016/S1359-6446(00)01558-0 Get rights and content

Abstract

Nucleoside analogue inhibitors of the reverse transcriptase (RT) enzyme of HIV-1 were the first class of compounds to be used in anti-HIV-1 therapy and are a cornerstone in highly active antiretroviral therapy. Despite the number of inhibitors of HIV-1 RT available for clinical use at the present time and the effectiveness of these compounds in combination regimens, long-term exposure of patients to these drugs often results in the development of viral resistance or long-term toxicity. For this reason, efforts to identify new agents with activity against drug-resistant strains of HIV-1 and with a toxicity profile that allows for individual patient tolerance of the drugs are still warranted.

Section snippets

Drugs in clinical development

The most important aspect of any new anti-HIV-1 agent, including NRTIs, is its ability to inhibit drug resistant strains of HIV. In addition, because multi-drug regimens form the existing paradigm for HIV-1 therapy, any new agent will inevitably be used in combination with other drugs and, therefore, not only has to be well tolerated, but needs to have minimal negative drug-interaction effects. At the present time, coviracil (FTC or emtricitabine), DAPD, tenofovir (the prodrug of PMPA), and

(−)dOTC

The dOTC (BioChem Pharma, Laval, Quebec, Canada) class of molecules are novel 4′-thio dideoxynucleoside analogues containing an oxygen heteroatom at the 3′- position of the sugar moiety (Fig. 1). The chemical synthesis and anti-HIV-1 properties of the racemate (+/−)dOTC or dOTC, as well as the individual enantiomers of dOTC [(+)dOTC and (−)dOTC] against HIV-1 in cell lines and primary cells have been reported⁵⁰. This class of 2,4-disubstituted 1,3-oxathiolane nucleosides is a hybrid of the

FddA (lodenosine)

The purine nucleoside lodenosine or FddA (US Bioscience, West Conshohocken, PA, USA; Fig. 1) was first reported by Marquez et al.⁵³ in 1987. FddA lacks potency in tissue culture assays against wild-type strains of HIV-1; however when tested against ddI- or AZT-resistant strains of virus, the potency is only minimally changed (2–3-fold change in IC₅₀)⁵⁴. The amino acid substitution most commonly associated with the change in phenotype to FddA is a switch from proline to serine at amino acid 119

Discovery pipeline

In light of the rate at which promising compounds drop out of drug development programs, HIV-1-infected individuals need new drugs that are well tolerated, economical and active against drug resistant strains of the virus. The list of compounds in preclinical or clinical development described previously might look impressive. However, on closer inspection, it is likely that only a few of them will (i) be approved for human use, and (ii) actually address the safety and efficacy needs of people

Summary

Nucleoside analogues were the first class of compounds approved for combating HIV-1 (as well as other viral) infections and they continue to have a major role in this regard. Unfortunately, the chronic nature of HIV-1 infection, along with the ability of the virus to mutate under selective pressure sets a tough standard for new antiretroviral agents: the drug must be well tolerated and effective against drug resistant strains of HIV-1. There are no clear strategies for identification of novel

Acknowledgements

We would like to thank Zhengxian Gu for help in producing Figure 2 and Andree Briseboise and Rachel Unger for help in preparation of this manuscript.

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ReviewDevelopment of novel nucleoside analogues for use against drug resistant strains of HIV-1

Abstract

Section snippets

Drugs in clinical development

(−)dOTC

FddA (lodenosine)

Discovery pipeline

Summary

Acknowledgements

Antiviral Res.

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An acid soluble purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol.

Adv. Drug Deliv. Rev.

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Antivral Chem. Chemother.

Didanosine: an update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease

Drugs

ddC (zalcitabine)

Adv. Exp. Med. Biol.

Lamivudine

Drugs Future

1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity

Antimicrob. Agents Chemother.

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Intervirology

Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase

Proc. Natl. Acad. Sci. U. S. A.

Effect of (−)2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerase α, β and γ

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Proc. Natl. Acad. Sci. U. S. A.

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Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT)

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Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant populations in persons treated with lamivudine (3TC)

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Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase

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High-level resistance to (−) enantiomeric 2′-deoxy-3′-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase

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Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility

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Review
Development of novel nucleoside analogues for use against drug resistant strains of HIV-1

Positive effects of combined antiretroviral therapy on CD₄⁺ T cell homeostasis and function in advanced HIV disease