Human immunodeficiency virus type 1 drug-resistance patterns with different 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives

Mol Pharmacol. 1993 Oct;44(4):694-701.


Of the class of the 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) derivatives, several congeners were found to inhibit (at 50% effective concentrations ranging from 0.02 to 0.6 microgram/ml) the replication of mutant human immunodeficiency virus type 1 (HIV-1) strains that had been selected for resistance against bis(heteroaryl)piperazine, tetrahydroimidazo[4,5,1-jk] [1,4]benzodiazepin-2(1H)-thiones (TIBO), nevirapine, [2',5'-bis-O-(tert- butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5''-(4''-amino- 1'',2'' -oxathiole-2'',2''-dioxide) (TSAO), or pyridinone and showed amino acid substitutions at positions 100, 103, 106, 138, and 181, respectively. When HIV-1 strains were selected for resistance against three different HEPT derivatives [i.e., HEPT and its derivatives 5-ethyl-1-ethoxymethyl-6-benzyluracil(E-EBU) and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil (EBU-dM)], HEPT selected for the mutation 188-Tyr-->His, E-EBU for 181-Tyr-->Cys, and E-EBU-dM for 106-Val-->Ala, in the reverse transcriptase of the mutant viruses. These virus strains showed markedly decreased sensitivity to HEPT derivatives. Moreover, the HEPT-resistant virus strains also proved cross-resistant to virtually all other HIV-1-specific inhibitors, including TIBO, nevirapine, and TSAO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Base Sequence
  • DNA Primers
  • Drug Resistance
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Polydeoxyribonucleotides / genetics
  • RNA-Directed DNA Polymerase / genetics
  • Reverse Transcriptase Inhibitors
  • Sensitivity and Specificity
  • Templates, Genetic
  • Thymine / analogs & derivatives*
  • Thymine / pharmacology


  • Antiviral Agents
  • DNA Primers
  • Polydeoxyribonucleotides
  • Reverse Transcriptase Inhibitors
  • 1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine
  • poly(dC-dG)
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Thymine