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.
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.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
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Z
Debyser
R
R
Pauwels
K
K
Andries
J
J
Desmyter
Y
Y
Engelborghs
P A
PA
Janssen
E
E
De Clercq
D001569:Benzodiazepines / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors
D007093:Imidazoles; D046911:Macromolecular Substances; D018894:Reverse Transcriptase Inhibitors; C062687:R 82150; D001569:Benzodiazepines; D012194:RNA-Directed DNA Polymerase