Resistance of human immunodeficiency virus type 1 reverse transcriptase to TIBO derivatives induced by site-directed mutagenesis

Virology. 1992 Jun;188(2):900-4. doi: 10.1016/0042-6822(92)90550-9.


The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is the target enzyme for the tetrahydro-imidazo[4,5,1-jk][1,4]- benzodiazepin-2(1H)one and thione (TIBO) derivatives, a class of highly potent and selective anti-HIV agents that specifically inhibit HIV-1 but not HIV-2 replication. The amino acid sequence divergence may be held responsible for the differential sensitivity of HIV-1 RT and HIV-2 RT to the TIBO derivatives. Using site-directed mutagenesis, we have introduced several amino acid substitutions in the conserved regions of HIV-1 RT. Where applicable, the amino acids were replaced by the corresponding amino acids present in HIV-2 RT. The amino acid residues Y181 and Y188 appeared to be critical for the anti-HIV-1 RT activity of the TIBO derivatives, since substitution of these residues by the corresponding HIV-2 amino acids I181 and L188 resulted in a virtual loss of TIBO sensitivity without loss of enzymatic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Benzodiazepines / pharmacology*
  • Binding Sites
  • Deoxyguanine Nucleotides / pharmacology
  • Dideoxynucleotides
  • HIV Reverse Transcriptase
  • HIV-1 / enzymology*
  • Imidazoles / pharmacology*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligodeoxyribonucleotides / chemistry
  • RNA-Directed DNA Polymerase / chemistry
  • Reverse Transcriptase Inhibitors*
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives
  • Uracil / pharmacology
  • Zidovudine / pharmacology


  • Antiviral Agents
  • Deoxyguanine Nucleotides
  • Dideoxynucleotides
  • Imidazoles
  • Oligodeoxyribonucleotides
  • Reverse Transcriptase Inhibitors
  • Benzodiazepines
  • 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil
  • Zidovudine
  • R-82913
  • Uracil
  • 2',3'-dideoxyguanosine 5'-triphosphate
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase