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Antimicrobial Agents and Chemotherapy, September 2007, p. 3162-3167, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00145-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Suppression of K65R Reverse Transcriptase-Mediated Tenofovir- and Adefovir-5'-Diphosphate Resistance Conferred by the Boranophosphonate Derivatives

Antoine Frangeul, Karine Barral, Karine Alvarez, and Bruno Canard^*

Centre National de la Recherche Scientifique and Universités d'Aix-Marseille I et II, UMR 6098, Architecture et Fonction des Macromolécules Biologiques, Ecole Supérieure d'Ingénieurs de Luminy-Case 925, 163 avenue de Luminy, 13288 Marseille cedex 9, France

Received 31 January 2007/ Returned for modification 16 March 2007/ Accepted 26 June 2007

9-[2-(Boranophosphonomethoxy)ethyl]adenine diphosphate (BH₃-PMEApp) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine diphosphate (BH₃-PMPApp), described here, represent the first nucleoside phosphonates modified on their -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. BH₃-PMEApp and BH₃-PMPApp exhibit the same inhibition properties as their nonborane analogues on WT RT. However, K65R RT was found hypersensitive to BH₃-PMEApp and as sensitive as WT RT to BH₃-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 BH₃-mediated suppression of HIV-1 RT resistance, formerly described with nucleoside 5'-(-p-borano)-triphosphate analogues, is thus also conserved at the phosphonate level. The present results show that an -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.

Published ahead of print on 9 July 2007.

These authors contributed equally.