Viral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase.
Thiazolo-iso-indolinone derivatives with high specificity toward the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) were identified. The most potent compound, BM +51.0836, inhibited HIV-1 RT at a 50% inhibitory concentration of 90 nM in vitro. In cell culture assays, similar 50% inhibitory concentrations were obtained with high specificity for HIV-1. These substances were equally active against a zidovudine-resistant isolate. No antiviral effect was observed with an HIV-2 isolate. HIV-1 isolates resistant to the thiazolo-iso-indolinones were generated in cell culture, and the nucleotide sequences of the respective RT genes were analyzed subsequently. Comparison of the deduced amino acid sequences with the wild-type sequence showed an amino acid change at position 181 (Tyr to Cys). Substitutions of amino acid Lys-101 and Lys-103 as well as Tyr-181 and/or Tyr-188 by site-directed mutagenesis led to resistance against the thiazolo-iso-indolinones. A chimeric HIV-2 RT, substituted with amino acids at positions 179 to 190 from HIV-1, acquired only partial susceptibility to BM +51.0836.
Maass
G
G
Bundesforschungsanstalt für Viruskrankheiten der Tiere, Tübingen, Germany.
Immendoerfer
U
U
Koenig
B
B
Leser
U
U
Mueller
B
B
Goody
R
R
Pfaff
E
E
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D004797:Enzyme-Linked Immunosorbent Assay; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D007211:Indoles; D054833:Isoindoles; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; C085888:BM 51.0836; C085887:BM 21.1298; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase