HIV-1 reverse transcriptase inhibition by a dipyridodiazepinone derivative: BI-RG-587.
The dipyridodiazepinone derivative 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]-[1,4] diazepin-6-one (BI-RG-587) selectively inhibits human immunodeficiency virus type 1 (HIV-1) replication by suppressing HIV-1 reverse transcriptase activity. Both RNA- and DNA-dependent polymerase associated activities of this enzyme were found to be inhibited by BI-RG-587 in a pattern dependent on the template used. The lowest IC50 values were obtained using poly(rC)-oligo(dG)12-18 and poly(dA)-oligo(dT)12-18 as template-primer. For the RNA-dependent activity poly(rC)-oligo(dG)12-18 and dGTP appeared to enhance the inhibition of the RNA-dependent enzyme activity by BI-RG-587, with the effect of poly(rC)-oligo(dG)12-18 dominating that of dGTP. Poly(rA)-oligo(dT)10 seemed to decrease the inhibition whereas poly(rU)-oligo(dA)12-18 or poly(rG)-oligo-(dC)12-18 had no effect. dATP, dTTP and dCTP, three nucleotide triphosphates, also had no impact on the inhibition. Differences were observed for the template-dependent action of BI-RG-587 against the DNA-dependent enzyme activity. Both substrates were required to allow the inhibition by BI-RG-587 in the poly(dC)-oligo(dG)12-18 and dGTP reaction, whereas only the template and enzyme interaction seemed to be necessary for the poly(dA)-oligo(dT)12-18 and dTTP reaction. The different behaviors of DNA- and RNA-dependent DNA polymerase activities could indicate either the presence of different active sites for distinct activities or the presence of a unique active site with different configurations depending upon the template used. Also, BI-RG-587 showed a mutually exclusive inhibition when combined with two other classes of HIV-1 RT inhibitors represented by phosphonoformic acid and 3'-azido-3'-dideoxythymidine triphosphate.
Tramontano
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Department of Pharmacology, School of Medicine, Yale University, New Haven, CT 06510.
Cheng
Y C
YC
D000998:Antiviral Agents / Q000494:pharmacology*; D017245:Foscarnet; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D019829:Nevirapine; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D017245:Foscarnet; D015215:Zidovudine; D019829:Nevirapine; D010746:Phosphonoacetic Acid