In vitro suppression of K65R reverse transcriptase-mediated tenofovir- and adefovir-5'-diphosphate resistance conferred by the boranophosphonate derivatives

Antimicrob Agents Chemother. 2007 Sep;51(9):3162-7. doi: 10.1128/AAC.00145-07. Epub 2007 Jul 9.


9-[2-(Boranophosphonomethoxy)ethyl]adenine diphosphate (BH(3)-PMEApp) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine diphosphate (BH(3)-PMPApp), described here, represent the first nucleoside phosphonates modified on their alpha-phosphates that act as efficient substrates for the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). These analogues were synthesized and evaluated for their in vitro activity against wild-type (WT), K65R, and R72A RTs. BH(3)-PMEApp and BH(3)-PMPApp exhibit the same inhibition properties as their nonborane analogues on WT RT. However, K65R RT was found hypersensitive to BH(3)-PMEApp and as sensitive as WT RT to BH(3)-PMPApp. Moreover, the presence of the borane group restores incorporation of the analogue by R72A HIV RT, the latter being nearly inactive with regular nucleotides. The BH(3)-mediated suppression of HIV-1 RT resistance, formerly described with nucleoside 5'-(alpha-p-borano)-triphosphate analogues, is thus also conserved at the phosphonate level. The present results show that an alpha-phosphate modification is also possible and interesting for phosphonate analogues, a result that might find application in the search for a means to control HIV RT-mediated drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Adenosine Triphosphate / metabolism
  • Boron Compounds / pharmacology*
  • Catalysis
  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • Drug Resistance, Viral / drug effects*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Mutation / genetics
  • Organophosphonates / pharmacology*
  • Plasmids / genetics
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Tenofovir


  • 9-(2-(boranophosphonomethoxy)ethyl)adenine
  • 9-(2-(boranophosphonomethoxy)propyl)adenine
  • Boron Compounds
  • Organophosphonates
  • Reverse Transcriptase Inhibitors
  • adefovir
  • Adenosine Triphosphate
  • Tenofovir
  • HIV Reverse Transcriptase
  • DNA-Directed RNA Polymerases
  • Adenine