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

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 tri...

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Bibliographic Details
Published in:	PloS one 2011-11, Vol.6 (11), p.e27456
Main Authors:	Vivet-Boudou, Valérie, Isel, Catherine, Sleiman, Marwan, Smyth, Redmond, Ben Gaied, Nouha, Barhoum, Patrick, Laumond, Géraldine, Bec, Guillaume, Götte, Matthias, Mak, Johnson, Aubertin, Anne-Marie, Burger, Alain, Marquet, Roland
Format:	Article
Language:	eng
Subjects:	Acquired immune deficiency syndrome Adenine AIDS Antiretroviral drugs Antiviral activity Biology Catalysis Cell culture Cell Line Chemistry Clinical trials Deoxyadenosine Deoxyadenosines - chemistry Deoxyadenosines - pharmacology Deoxyadenosines - therapeutic use Deoxyribonucleic acid DNA DNA biosynthesis DNA synthesis Drug Design Drug development Drug resistance Drugs Enzymes Genetic transcription HIV HIV (Viruses) HIV Reverse Transcriptase - drug effects HIV Reverse Transcriptase - metabolism HIV-1 - drug effects Human immunodeficiency virus Humans Medical research Medicine Monosaccharides Mutation Nucleoside analogs Nucleosides Polymerization Reverse transcription Ribose Structure-Activity Relationship Sugars Termination (polymerization) Transcription (Genetics) Virology Virus replication Virus Replication - drug effects Viruses
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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.
ISSN:	1932-6203 1932-6203