title: In vitro suppression of K65R reverse transcriptase-mediated tenofovir- and adefovir-5'-diphosphate resistance conferred by the boranophosphonate derivatives.
abstract: 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.
authors.affiliation: AFMB-CNRS-ESIL, Case 925, 163 avenue de Luminy, 13288 Marseille Cedex 9, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Frangeul
authors.forename: Karine
authors.initials: K
authors.lastname: Barral
authors.forename: Karine
authors.initials: K
authors.lastname: Alvarez
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology*; D002384:Catalysis; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D024882:Drug Resistance, Viral / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation / Q000235:genetics; D063065:Organophosphonates / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir
chemical_list: C516687:9-(2-(boranophosphonomethoxy)ethyl)adenine; C516688:9-(2-(boranophosphonomethoxy)propyl)adenine; D001896:Boron Compounds; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; C053001:adefovir; D000255:Adenosine Triphosphate; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D012321:DNA-Directed RNA Polymerases; D000225:Adenine