Publications & Reports

8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

Vivet-Boudou V, Isel C, Sleiman M, Smyth R, Ben Gaied N, Barhoum P, Laumond G, Bec G, Götte M, Mak J, Aubertin AM, Burger A, Marquet R
Architecture et Reactivite de l'ARN, Institut de Biologie Moleculaire et Cellulaire, Universite de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France. v.vivet@ibmc-cnrs.unistra.fr

Abstract

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix alphaH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.

Publication

  • Journal: PloS One
  • Published: 07/11/2011
  • Volume: 6
  • Issue: 11
  • Pagination: e27456

Health Issue

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