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

Vivet-Boudou, Valerie, Isel, Catherine, Sleiman, Marwan, Smyth, Redmond, Ben-Gaied, Nouha, Barhoum, Patrick, Laumond, Geraldine, Bec, Guillaume, Gotte, Matthias, Mak, Johnson, Aubertin, Anne-Marie, Burger, Alain and Marquet, Roland 2011, 8-modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription, PLoS one, vol. 6, no. 11, pp. 1-12, doi: 10.1371/journal.pone.0027456.

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Title 8-modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription
Author(s) Vivet-Boudou, Valerie
Isel, Catherine
Sleiman, Marwan
Smyth, Redmond
Ben-Gaied, Nouha
Barhoum, Patrick
Laumond, Geraldine
Bec, Guillaume
Gotte, Matthias
Mak, JohnsonORCID iD for Mak, Johnson orcid.org/0000-0002-5229-5707
Aubertin, Anne-Marie
Burger, Alain
Marquet, Roland
Journal name PLoS one
Volume number 6
Issue number 11
Start page 1
End page 12
Total pages 12
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2011-11-07
ISSN 1932-6203
Keyword(s) cell line
deoxyadenosines
drug design
HIV reverse transcriptase
HIV-1
humans
structure-activity relationship
virus replication
Summary 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.
Language eng
DOI 10.1371/journal.pone.0027456
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2011, Public Library of Science
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047592

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.