title: Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5 "- (4"-amino-1",2"-oxathiole-2",2"-dioxide)thymine (TSAO-T).
abstract: [2',5'-Bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro- 5"-(4"-amino-1",2"-oxathiole-2", 2"-dioxide)thymine (TSAO-T) is a representative of a novel class of nucleoside analogues that are endowed with a potent and specific activity against human immunodeficiency virus (HIV) type 1 and are targeted at the HIV-1 reverse transcriptase (RT). Inhibition of HIV-1 RT by TSAO-T was reversible and noncompetitive with respect to dGTP as the substrate and poly(C).oligo(dG) as the template/primer. In contrast with the nonnucleoside derivatives tetrahydroimidazo-[4,5,1-jk][1,4]- benzodiazepin-2(1H)-thione (TIBO) (R-82150), nevirapine (BI-RG-587) and the HEPT derivative I-HEPU-SdM, TSAO-T was not inhibitory to HIV-1 RT in the presence of other homopolymeric template/primers. It did not interfere with the DNA-dependent DNA polymerase function of HIV-1 RT, HIV-2 RT, herpes simplex virus type 1 DNA polymerase, or Taq polymerase. However, TSAO-T proved inhibitory to the HIV-1 RT reaction primed by Escherichia coli 16S/23S rRNA, irrespective of the nature of the radiolabeled 2'-deoxynucleotide 5'-triphosphate (dNTP) used. TSAO-T does not act as a DNA chain terminator. It interacts with HIV-1 RT at a nonsubstrate (dNTP)-binding site.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: A
authors.initials: A
authors.lastname: San-Félix
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: I C
authors.initials: IC
authors.lastname: Bathurst
authors.forename: P J
authors.initials: PJ
authors.lastname: Barr
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D003848:Deoxyguanine Nucleotides / Q000494:pharmacology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D001583:Benzoxazoles; D003848:Deoxyguanine Nucleotides; D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C062687:R 82150; D001569:Benzodiazepines; C070357:L 697639; C075133:5-isopropyl-1-((hydroxyethoxy)methyl)-6-(3,5-dimethylphenythio)-2-thiouracil; D013889:Thiouracil; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase