Open AccessViral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase
Author(s) -
G. Maaß,
U Immendoerfer,
Bernd W. Koenig,
Ulrike Leser,
Bettina Mueller,
Roger S. Goody,
Eberhard Pfaff
Publication year - 1993
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.37.12.2612
Subject(s) - zidovudine , reverse transcriptase , virus , mutagenesis , amino acid , biology , virology , in vitro , chemistry , microbiology and biotechnology , gene , biochemistry , mutation , polymerase chain reaction , viral disease
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.