Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′-triphosphate metabolite levels

Jan Balzarini, Stefano Aquaro, Alshaimaa Hassan-Abdallah, Susan M. Daluge, Carlo Federico Perno, Chris McGuigan

Research output: Contribution to journalArticle

Abstract

The anti-human immunodeficiency virus (HIV) activity of abacavir (ABC; 1-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1- methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro-ABC-MP) to virus-infected cell cultures. Metabolic studies with radiolabeled ABC and pro-ABC-MP in human T-lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC-MP) by pro-ABC-MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5-triphosphate (CBV-TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC-MP and appearance of CBV-TP closely correlated with the extracellular pro-ABC-MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 μM. The highest amounts of CBV-TP were observed within 6-24 h after drug administration. The improved delivery of ABC-MP and metabolic conversion to CBV-TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy.

Original languageEnglish
Pages (from-to)38-44
Number of pages7
JournalFEBS Letters
Volume573
Issue number1-3
DOIs
Publication statusPublished - Aug 27 2004

Keywords

  • ABC, abacavir
  • ABC-MP, ABC-5-monophosphate
  • CBV, carbovir
  • CBV-DP, CBV-5-diphosphate
  • CBV-MP, CBV-5-monophosphate
  • CBV-TP, CBV-5- triphosphate

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Fingerprint Dive into the research topics of 'Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′-triphosphate metabolite levels'. Together they form a unique fingerprint.

  • Cite this