BIOMAT Database Logo BIOMAT Database Logo

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. 1992

Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

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.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D007700 Kinetics The rate dynamics in chemical or physical systems.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001569 Benzodiazepines A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. Benzodiazepine,Benzodiazepine Compounds
D012194 RNA-Directed DNA Polymerase An enzyme that synthesizes DNA on an RNA template. It is encoded by the pol gene of retroviruses and by certain retrovirus-like elements. EC 2.7.7.49. DNA Polymerase, RNA-Directed,RNA-Dependent DNA Polymerase,Reverse Transcriptase,RNA Transcriptase,Revertase,DNA Polymerase, RNA Directed,DNA Polymerase, RNA-Dependent,RNA Dependent DNA Polymerase,RNA Directed DNA Polymerase
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D046911 Macromolecular Substances Compounds and molecular complexes that consist of very large numbers of atoms and are generally over 500 kDa in size. In biological systems macromolecular substances usually can be visualized using ELECTRON MICROSCOPY and are distinguished from ORGANELLES by the lack of a membrane structure. Macromolecular Complexes,Macromolecular Compounds,Macromolecular Compounds and Complexes,Complexes, Macromolecular,Compounds, Macromolecular,Substances, Macromolecular
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse

Related Publications

Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Kinetic interaction of human immunodeficiency virus type 1 reverse transcriptase with the antiviral tetrahydroimidazo[4,5,1-jk]-[1,4]-benzodiazepine-2-(1H)-thione compound, R82150.
August 1991, The Journal of biological chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TIBO) derivatives.
February 1991, Journal of medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
March 2005, Journal of medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TlBO) derivatives. 4.
March 1995, Journal of medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 3.
March 1995, Journal of medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1- jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150).
January 1993, Molecular pharmacology,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-on e (TIBO) derivatives. 2.
November 1991, Journal of medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Synthesis and anti-HIV activity of 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (TBO) derivatives. Truncated 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2( 1H)-on es (TIBO) analogues.
November 1999, Bioorganic & medicinal chemistry,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Inhibition of human immunodeficiency virus type I reverse transcriptase by suramin-related compounds.
August 1987, The Journal of general virology,
Z Debyser, and R Pauwels, and K Andries, and J Desmyter, and Y Engelborghs, and P A Janssen, and E De Clercq
Human Immunodeficiency Virus type 1 reverse transcriptase.
February 1996, Biological chemistry Hoppe-Seyler,
Copied contents to your clipboard!