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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. 1993

J Balzarini, and S Velazquez, and A San-Felix, and A Karlsson, and M J Perez-Perez, and M J Camarasa, and E De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

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.

UI MeSH Term Description Entries
D007042 Hypoxanthines Purine bases related to hypoxanthine, an intermediate product of uric acid synthesis and a breakdown product of adenine catabolism.
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D004351 Drug Resistance Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. Resistance, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D001483 Base Sequence The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence. DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D012194 RNA-Directed DNA Polymerase An enzyme that synthesizes DNA on an RNA template. It is encoded by the pol gene of retroviruses and by certain retrovirus-like elements. EC 2.7.7.49. DNA Polymerase, RNA-Directed,RNA-Dependent DNA Polymerase,Reverse Transcriptase,RNA Transcriptase,Revertase,DNA Polymerase, RNA Directed,DNA Polymerase, RNA-Dependent,RNA Dependent DNA Polymerase,RNA Directed DNA Polymerase
D013141 Spiro Compounds Cyclic compounds that include two rings which share a single atom (usually a carbon). The simplest example of this type of compound is Spiro[2.2]pentane, which looks like a bow tie. Compounds, Spiro

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