title: Resistance of human immunodeficiency virus type 1 reverse transcriptase to TIBO derivatives induced by site-directed mutagenesis.
abstract: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is the target enzyme for the tetrahydro-imidazo[4,5,1-jk][1,4]- benzodiazepin-2(1H)one and thione (TIBO) derivatives, a class of highly potent and selective anti-HIV agents that specifically inhibit HIV-1 but not HIV-2 replication. The amino acid sequence divergence may be held responsible for the differential sensitivity of HIV-1 RT and HIV-2 RT to the TIBO derivatives. Using site-directed mutagenesis, we have introduced several amino acid substitutions in the conserved regions of HIV-1 RT. Where applicable, the amino acids were replaced by the corresponding amino acids present in HIV-2 RT. The amino acid residues Y181 and Y188 appeared to be critical for the anti-HIV-1 RT activity of the TIBO derivatives, since substitution of these residues by the corresponding HIV-2 amino acids I181 and L188 resulted in a virtual loss of TIBO sensitivity without loss of enzymatic activity.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: de Vreese
authors.forename: Z
authors.initials: Z
authors.lastname: Debyser
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
authors.forename: J
authors.initials: J
authors.lastname: Anné
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D003848:Deoxyguanine Nucleotides / Q000494:pharmacology; D054306:Dideoxynucleotides; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D003848:Deoxyguanine Nucleotides; D054306:Dideoxynucleotides; D007093:Imidazoles; D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; C071166:5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil; D015215:Zidovudine; C067413:R-82913; D014498:Uracil; C031709:2',3'-dideoxyguanosine 5'-triphosphate; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase