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

Mol Pharmacol. 1993 Jan;43(1):109-14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Drug Resistance
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • Humans
  • Hypoxanthines / pharmacology*
  • Molecular Sequence Data
  • Mutation
  • RNA-Directed DNA Polymerase / genetics
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Thymidine / analogs & derivatives
  • Thymidine / pharmacology
  • Uridine / analogs & derivatives


  • Antiviral Agents
  • Hypoxanthines
  • Spiro Compounds
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Thymidine
  • TSAO-T
  • Uridine