Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors

Science. 1995 Feb 17;267(5200):988-93. doi: 10.1126/science.7532321.

Abstract

The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly (Kd, 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology*
  • Binding Sites
  • DNA / metabolism
  • Deoxyadenine Nucleotides / metabolism
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Kinetics
  • Magnesium / metabolism
  • Magnesium / pharmacology
  • Nevirapine
  • Protein Conformation
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • RNA-Directed DNA Polymerase / chemistry
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors*

Substances

  • Antiviral Agents
  • Deoxyadenine Nucleotides
  • Imidazoles
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • Benzodiazepines
  • R 79882
  • R 82913
  • DNA
  • Nevirapine
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Magnesium
  • 2'-deoxyadenosine triphosphate