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.


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.


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

Health Issue