Differences in the inhibition of human immunodeficiency virus type 1 reverse transcriptase DNA polymerase activity by analogs of nevirapine and [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1", 2"-oxathiole-2",2"-dioxide] (TSAO)

Mol Pharmacol. 1996 Nov;50(5):1057-64.


We compared the inhibition of HIV-1 reverse transcriptase (RT) by 1-[2',5'-bis-O-(t-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'- spiro-5"-(4"-amino-1", 2"-oxathiole-2",2"-dioxide)-3-ethylthymine (TSAOe3T) and the nonnucleoside RT inhibitor (NNRTI) 9-aminonevirapine (9-NH2N). Both compounds were equally effective against p51/p66 heterodimeric RT RNA-dependent DNA polymerase activity, although TSAOe3T was a much better inhibitor of the p51/p51 and p66/p66 RT homodimers. Inhibition by TSAOe3T and 9-NH2N combinations was essentially additive. TSAOe3T did not protect either free RT or the RT-template/ primer-deoxynucleoside triphosphate ternary complex from irreversible inactivation by the photolabel 9-azidonevirapine. Slight protection of the RT-template/primer binary complex was noted, but only at high TSAOe3T/photolabel ratios. Analysis of RT polymerization product profiles under both continuous- and single-processive cycle conditions showed that 9-NH2N prevented the formation of full-length product with a corresponding accumulation of smaller polymerization products. In contrast, all products formed in the absence of inhibitor, including full-length product, were noted in TSAOe3T-inhibited reactions, albeit at reduced levels. TSAOe3T thus inhibits HIV-1 RT by a different mechanism than NNRTI such as nevirapine. Our data suggest that TSAOe3T and 9-NH2N interact differently with HIV-1 RT, perhaps by binding to distinct sites on the enzyme.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology*
  • Binding Sites
  • DNA-Directed DNA Polymerase / metabolism
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Kinetics
  • Nucleic Acid Synthesis Inhibitors*
  • Photochemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • RNA-Directed DNA Polymerase / drug effects
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Thymidine / analogs & derivatives*
  • Thymidine / metabolism
  • Thymidine / pharmacology


  • 1-(2',5'-bis-O-(t-butyldimethylsilyl)ribofuranosyl)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)-3-ethylthymine
  • 9-aminonevirapine
  • Antiviral Agents
  • Nucleic Acid Synthesis Inhibitors
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • Spiro Compounds
  • Benzodiazepines
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • DNA-Directed DNA Polymerase
  • Thymidine