Selectivity of kinases on the activation of tenofovir, an anti-HIV agent

A. Varga, Éva Gráczer, Laurent Chaloin, K. Liliom, P. Závodszky, Corinne Lionne, M. Vas

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Nucleoside analogues, used in HIV-therapy, need to be phosphorylated by cellular enzymes in order to become potential substrates for HIV reverse transcriptase. After incorporation into the viral DNA chain, because of lacking of their 3'-hydroxyl groups, they stop the elongation process and lead to the death of the virus. Phosphorylation of the HIV-drug derivative, tenofovir monophosphate was tested with the recombinant mammalian nucleoside diphosphate kinase (NDPK), 3-phosphoglycerate kinase (PGK), creatine kinase (CK) and pyruvate kinase (PK). Among them, only CK was found to phosphorylate tenofovir monophosphate with a reasonable rate (about 45-fold lower than with its natural substrate, ADP), while PK exhibits even lower, but still detectable activity (about 1000-fold lower compared to the value with ADP). On the other hand, neither NDPK nor PGK has any detectable activity on tenofovir monophosphate. The absence of activity with PGK is surprising, since the drug tenofovir competitively inhibits both CK and PGK towards their nucleotide substrates, with similar inhibitory constants, KI of 2.9 and 4.8 mM, respectively. Computer modelling (docking) of tenofovir mono- or diphosphate forms to these four kinases suggests that the requirement of large-scale domain closure for functioning (as for PGK) may largely restrict their applicability for phosphorylation/activation of pro-drugs having a structure similar to tenofovir monophosphate.

Original languageEnglish
Pages (from-to)307-315
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Volume48
Issue number1-2
DOIs
Publication statusPublished - Jan 23 2013

Fingerprint

Tenofovir
Anti-HIV Agents
Phosphoglycerate Kinase
Phosphotransferases
Creatine Kinase
Pyruvate Kinase
Adenosine Diphosphate
NM23 Nucleoside Diphosphate Kinases
Nucleoside-Diphosphate Kinase
Phosphorylation
HIV
HIV Reverse Transcriptase
Diphosphates
Viral DNA
Prodrugs
Nucleosides
Pharmaceutical Preparations
Hydroxyl Radical
Nucleotides

Keywords

  • 3-Phospho-D-glycerate kinase
  • Creatine kinase
  • Nucleoside diphosphate kinase
  • Pyruvate kinase
  • Tenofovir

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Selectivity of kinases on the activation of tenofovir, an anti-HIV agent. / Varga, A.; Gráczer, Éva; Chaloin, Laurent; Liliom, K.; Závodszky, P.; Lionne, Corinne; Vas, M.

In: European Journal of Pharmaceutical Sciences, Vol. 48, No. 1-2, 23.01.2013, p. 307-315.

Research output: Contribution to journalArticle

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