title: 8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.
abstract: 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.
authors.affiliation: Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France. v.vivet@ibmc-cnrs.unistra.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Vivet-Boudou
authors.forename: Catherine
authors.initials: C
authors.lastname: Isel
authors.forename: Marwan
authors.initials: M
authors.lastname: Sleiman
authors.forename: Redmond
authors.initials: R
authors.lastname: Smyth
authors.forename: Nouha
authors.initials: N
authors.lastname: Ben Gaied
authors.forename: Patrick
authors.initials: P
authors.lastname: Barhoum
authors.forename: Géraldine
authors.initials: G
authors.lastname: Laumond
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bec
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Johnson
authors.initials: J
authors.lastname: Mak
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Aubertin
authors.forename: Alain
authors.initials: A
authors.lastname: Burger
authors.forename: Roland
authors.initials: R
authors.lastname: Marquet
mesh_terms: D002460:Cell Line; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D003839:Deoxyadenosines; D054303:HIV Reverse Transcriptase; C058118:2'-deoxyadenosine
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