title: Human immunodeficiency virus type 1-specific [2',5'-bis-O-(tert- butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)-purine analogues show a resistance spectrum that is different from that of the human immunodeficiency virus type 1-specific non-nucleoside analogues.
abstract: The [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'- spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) (TSAO) derivatives of N1-methylhypoxanthine with linkage to the TSAO moiety through the N9 or N7 atom of the hypoxanthine ring (designated TSAO-m1Hx and 7-TSAO-m1Hx, respectively) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) but not HIV-2 or simian immunodeficiency virus. Their selectivity indices (ratio of cytotoxic concentration to antivirally active concentration) are > 500. This is a > 15-fold increase in therapeutic index, compared with TSAO-adenine. A HIV-1(IIIB) variant selected for resistance to TSAO-m1Hx (designated HIV-1/TSAO-m1Hx) proved to be cross-resistant to the other TSAO-purine derivatives and to the TSAO-pyrimidine derivatives. However, HIV-1/TSAO-m1Hx was highly sensitive to the HIV-1-specific non-nucleoside tetrahydroimidazobenzodiazepinone, nevirapine, pyridinone L697,661, and several HEPT derivatives. The reverse transcriptase (RT) of HIV-1/TSAO-m1Hx shows a single amino acid change (138-Glu to Lys) that is identical to the amino acid change that has recently been observed in several HIV-1/TSAO-pyrimidine mutant strains. Our observations indicate that the TSAO-purines and TSAO-pyrimidines belong to one pharmacological class of HIV-1-specific RT inhibitors that are targeted at the same molecular site of the HIV-1 RT.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: S
authors.initials: S
authors.lastname: Velazquez
authors.forename: A
authors.initials: A
authors.lastname: San-Felix
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
authors.forename: M J
authors.initials: MJ
authors.lastname: Perez-Perez
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004351:Drug Resistance; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007042:Hypoxanthines / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D013141:Spiro Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D007042:Hypoxanthines; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine