In vitro Suppression of K65R Reverse Transcriptase-mediated Tenofovir- and Adefovir-5' Diphosphate Resistance Conferred by the Borano-phosphonate Derivatives

From the 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

^* To whom correspondence should be addressed. Email: Bruno.Canard{at}afmb.univ-mrs.fr.

	Abstract

The 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 -phosphate, that act as efficient substrates for the Human Immunodeficiency Virus Reverse Transcriptase (HIV-1 RT). These analogues were synthesized and evaluated for their in vitro activity against wild-type, K65R, and R72A RT. BH₃-PMEApp and BH₃-PMPApp exhibit the same inhibition properties as their non-borano analogues on wild-type (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 borano 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 of control of HIV-RT-mediated drug resistance.