Alpha-carboxynucleoside phosphonates: Direct-acting inhibitors of viral DNA polymerases

Jan Balzarini, Alan Ford, Nuala M. Maguire, Jubi John, Kalyan Das, Eddy Arnold, Wim Dehaen, Anita Maguire

Research output: Contribution to journalReview article

1 Scopus citations

Abstract

Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2′-deoxynucleotide 5′-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.

Original languageEnglish (US)
Pages (from-to)137-154
Number of pages18
JournalFuture Medicinal Chemistry
Volume11
Issue number2
DOIs
StatePublished - Jan 2019

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Keywords

  • HIV
  • acyclic nucleoside phosphonate (ANP)
  • chemotherapeutics
  • herpesviruses
  • nucleoside-analog inhibitor
  • reverse transcriptase (RT)
  • viral DNA polymerase
  • α-carboxynucleoside phosphonate (α-CNP)

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  • Cite this

    Balzarini, J., Ford, A., Maguire, N. M., John, J., Das, K., Arnold, E., Dehaen, W., & Maguire, A. (2019). Alpha-carboxynucleoside phosphonates: Direct-acting inhibitors of viral DNA polymerases. Future Medicinal Chemistry, 11(2), 137-154. https://doi.org/10.4155/fmc-2018-0324