title: Comparative evaluation of seven oligonucleotide analogues as potential antisense agents.
abstract: 12-Mer analogues, representative of seven different classes of structurally modified oligonucleotides and complementary to the same target, have been compared for their binding affinity for both single-stranded DNA and RNA, resistance to hydrolysis by nucleases in culture medium (RPMI 1640 + 10% inactivated fetal calf serum), and inhibition of HIV-1 replication in de novo infected MT4 T lymphocytes. The viral target was the splice acceptor site of the premessenger coding for the regulatory protein tat. The oligo(2'-O-alkyl)ribonucleotides (beta-2'O-allyl-RNA and beta-2'OMe-RNA) were shown to form the most stable hybrids with complementary RNA strands whereas the alpha-anomeric oligodeoxynucleoside phosphorothioate analogue displayed the highest stability in the culture medium. All the modified oligonucleotides examined in the present study exhibited a sequence-nonspecific inhibitory effect on HIV-1 replication, the phosphorothioate analogues being the most active ones (ED50 < 1 microM).
authors.affiliation: Laboratoire de Chimie Bio-Organique, URA 488 du CNRS, Université de Montpellier II, France.
authors.forename: F
authors.initials: F
authors.lastname: Morvan
authors.forename: H
authors.initials: H
authors.lastname: Porumb
authors.forename: G
authors.initials: G
authors.lastname: Degols
authors.forename: I
authors.initials: I
authors.lastname: Lefebvre
authors.forename: A
authors.initials: A
authors.lastname: Pompon
authors.forename: B S
authors.initials: BS
authors.lastname: Sproat
authors.forename: B
authors.initials: B
authors.lastname: Rayner
authors.forename: C
authors.initials: C
authors.lastname: Malvy
authors.forename: B
authors.initials: B
authors.lastname: Lebleu
authors.forename: J L
authors.initials: JL
authors.lastname: Imbach
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016376:Oligonucleotides, Antisense