Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors

J Biol Chem. 1992 Sep 5;267(25):17526-30.


Several novel, structurally distinct classes of specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) nonnucleoside inhibitors have been described recently. These include the pyridinone derivatives L-697,639, L-697,661, and L-696,229 as well as BI-RG-587 and the tetrahydroimidazo[4,5,1-j,k]-benzodiazepin-2(1H)-one and -thione compounds. Previous studies have implicated involvement of the RT amino acid residues at positions 103, 181, and 188 in the activity of the compounds. Accordingly, HIV-1 RT mutants containing a series of amino acid substitutions at these positions were constructed. The relative resistance of purified mutant enzymes to each of the inhibitors was assessed. This analysis established the functional equivalence of the three inhibitor classes and provided evidence for the interaction of the 103 site with the 181/188 region. Amino acid substitutions at these positions were also found to influence RT sensitivity to inhibition by phosphonoformate, thereby suggesting a close association between this pyrophosphate analog's binding site in RT and the binding site of the nonnucleoside inhibitors. In addition, aromatic stacking of the amino acid side groups at residues 181 and 188 was suggested to be required for inhibitor activity.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / pharmacology*
  • Azepines / pharmacology
  • Benzodiazepines / pharmacology
  • Benzoxazoles / pharmacology
  • Drug Resistance, Microbial / genetics
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Imidazoles / pharmacology
  • Kinetics
  • Mutagenesis, Site-Directed
  • Nevirapine
  • Pyridines / pharmacology
  • Pyridones / pharmacology
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / isolation & purification
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / isolation & purification
  • Reverse Transcriptase Inhibitors*
  • Structure-Activity Relationship


  • Antiviral Agents
  • Azepines
  • Benzoxazoles
  • Imidazoles
  • Pyridines
  • Pyridones
  • Recombinant Proteins
  • Reverse Transcriptase Inhibitors
  • Benzodiazepines
  • L 696229
  • L 697639
  • L 697661
  • R 82913
  • Nevirapine
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase