Viral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase

Antimicrob Agents Chemother. 1993 Dec;37(12):2612-7. doi: 10.1128/AAC.37.12.2612.


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.

MeSH terms

  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Cells, Cultured
  • Drug Resistance, Microbial
  • Enzyme-Linked Immunosorbent Assay
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / physiology
  • Humans
  • Indoles / pharmacology*
  • Isoindoles
  • Molecular Sequence Data
  • Mutation / genetics
  • RNA-Directed DNA Polymerase / genetics
  • Recombinant Fusion Proteins / genetics
  • Reverse Transcriptase Inhibitors*
  • Thiazoles / pharmacology*
  • Virus Replication / drug effects


  • Antiviral Agents
  • Indoles
  • Isoindoles
  • Recombinant Fusion Proteins
  • Reverse Transcriptase Inhibitors
  • Thiazoles
  • BM 51.0836
  • BM 21.1298
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase