title: An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives.
abstract: Screening of pharmacologically acceptable prototype compounds has recently led to the discovery of a series of ultraselective inhibitors of human immunodeficiency virus (HIV)-1 replication, the tetrahydroimidazo[4,5,1-jk] [1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives. The TIBO compounds completely suppress the formation of proviral DNA in acutely infected cells, as revealed by polymerase chain reaction (PCR) analysis. TIBO derivatives are inhibitory to the reverse transcriptase (RT) of HIV-1 but not that of HIV-2 or other retroviruses. The inhibition is most effective with poly(C)-oligo(dG) as the template/primer, and it is selectively directed against the RNA-dependent DNA polymerase activity and not the accompanying DNA-dependent DNA polymerase and ribonuclease H activity of HIV-1 RT. Kinetic studies point to an uncompetitive inhibition with regard to the template/primer. TIBO compounds are active against HIV-1 replication through a unique interaction with HIV-1 RT. The experimental data indicate the existence of a target on HIV-1 RT that is responsible for the inhibition of replication and a mode of action unrelated to that of previously studied RT inhibitors.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: Z
authors.initials: Z
authors.lastname: Debyser
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: K
authors.initials: K
authors.lastname: Andries
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: M
authors.initials: M
authors.lastname: Kukla
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; C062687:R 82150; D001569:Benzodiazepines; C067413:R-82913