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

• 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: English
• 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; HIV; 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; Termination (polymerization); Transcription (Genetics); Virology; Virus replication; Virus Replication - drug effects; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027456

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.