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

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journal contribution
posted on 2011-11-07, 00:00 authored by V Vivet-Boudou, C Isel, M Sleiman, R Smyth, N Ben-Gaied, P Barhoum, G Laumond, G Bec, M Gotte, Johnson Mak, A M Aubertin, A Burger, R Marquet
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 αH 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.

History

Journal

PLoS one

Volume

6

Issue

11

Pagination

1 - 12

Publisher

Public Library of Science

Location

San Francisco, Calif.

ISSN

1932-6203

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2011, Public Library of Science