Human immunodeficiency virus type 1 drug-resistance patterns with different 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives.
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.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium.
Karlsson
A
A
De Clercq
E
E
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004351:Drug Resistance; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011089:Polydeoxyribonucleotides / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D012680:Sensitivity and Specificity; D013698:Templates, Genetic; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D017931:DNA Primers; D011089:Polydeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; C019530:poly(dC-dG); D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D013941:Thymine