Intracellular metabolism of nucleoside/nucleotide analogues

A bottleneck to reach active drugs on HIV reverse transcriptase

A. Varga, Corinne Lionne, Béatrice Roy

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3′-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

Original languageEnglish
Pages (from-to)237-252
Number of pages16
JournalCurrent Drug Metabolism
Volume17
Issue number3
Publication statusPublished - Mar 1 2016

Fingerprint

HIV Reverse Transcriptase
Nucleosides
Metabolism
Nucleotides
Phosphorylation
Reverse Transcriptase Inhibitors
Pharmaceutical Preparations
Nucleotidases
Integrases
Molecules
Highly Active Antiretroviral Therapy
Viral DNA
Protease Inhibitors
Hydroxyl Radical
Machinery
Phosphotransferases
HIV

Keywords

  • HIV
  • Nucleoside/nucleotide analogues
  • Nucleoside/nucleotide kinase
  • Nucleotidase
  • Phosphorylation
  • Reverse transcriptase

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this

Intracellular metabolism of nucleoside/nucleotide analogues : A bottleneck to reach active drugs on HIV reverse transcriptase. / Varga, A.; Lionne, Corinne; Roy, Béatrice.

In: Current Drug Metabolism, Vol. 17, No. 3, 01.03.2016, p. 237-252.

Research output: Contribution to journalArticle

@article{36ed0f3a9697473396f4cc51429dd000,
title = "Intracellular metabolism of nucleoside/nucleotide analogues: A bottleneck to reach active drugs on HIV reverse transcriptase",
abstract = "Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3′-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.",
keywords = "HIV, Nucleoside/nucleotide analogues, Nucleoside/nucleotide kinase, Nucleotidase, Phosphorylation, Reverse transcriptase",
author = "A. Varga and Corinne Lionne and B{\'e}atrice Roy",
year = "2016",
month = "3",
day = "1",
language = "English",
volume = "17",
pages = "237--252",
journal = "Current Drug Metabolism",
issn = "1389-2002",
publisher = "Bentham Science Publishers B.V.",
number = "3",

}

TY - JOUR

T1 - Intracellular metabolism of nucleoside/nucleotide analogues

T2 - A bottleneck to reach active drugs on HIV reverse transcriptase

AU - Varga, A.

AU - Lionne, Corinne

AU - Roy, Béatrice

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3′-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

AB - Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3′-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

KW - HIV

KW - Nucleoside/nucleotide analogues

KW - Nucleoside/nucleotide kinase

KW - Nucleotidase

KW - Phosphorylation

KW - Reverse transcriptase

UR - http://www.scopus.com/inward/record.url?scp=84959889377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959889377&partnerID=8YFLogxK

M3 - Article

VL - 17

SP - 237

EP - 252

JO - Current Drug Metabolism

JF - Current Drug Metabolism

SN - 1389-2002

IS - 3

ER -