Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds

Mol Pharmacol. 1992 Jan;41(1):203-8.

Abstract

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is present in virions and infected cells as an heterodimer (p66/p51). A new class of potent and selective HIV-1 inhibitors, the tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, were found to exert their antiviral activity by interacting with monomeric HIV-1 RT (p66) in a way different from that of previously studied RT inhibitors such as azidothymidine 5'-triphosphate. Upon examination of the kinetic properties of the heterodimeric HIV-1 RT and its inhibition by TIBO compounds, a positive cooperativity between the subunits of the enzyme with regard to the 2'-deoxynucleoside 5'-triphosphates and the template/primer was observed. The cooperativity with respect to the template/primer may result from a progressive dimerization in the presence of increasing concentrations of the template/primer, a process referred to as polysteric linkage. Because the cooperativity of p66/p51 was abolished in the presence of TIBO, these compounds behave as allosteric inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodiazepines / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Imidazoles / pharmacology*
  • Kinetics
  • Macromolecular Substances
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors*

Substances

  • Imidazoles
  • Macromolecular Substances
  • Reverse Transcriptase Inhibitors
  • R 82150
  • Benzodiazepines
  • RNA-Directed DNA Polymerase