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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.
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https://hal-amu.archives-ouvertes.fr/hal-02061675
Contributor : Karine Barral Connect in order to contact the contributor
Submitted on : Friday, March 8, 2019 - 11:53:00 AM
Last modification on : Wednesday, December 8, 2021 - 3:50:18 AM

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A. Frangeul, Karine Barral, K. Alvarez, B. Canard. In Vitro Suppression of K65R Reverse Transcriptase-Mediated Tenofovir- and Adefovir-5'-Diphosphate Resistance Conferred by the Boranophosphonate Derivatives. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2007, 51 (9), pp.3162-3167. ⟨10.1128/AAC.00145-07⟩. ⟨hal-02061675⟩

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