A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site.
A novel dipyridodiazepinone, 6,11-dihydro-11-cyclopropyl-4-methyldipyrido[2,3-b:2',3'-e]- [1,4]diazepin-6-one (BI-RG-587), is a selective noncompetitive inhibitor of HIV-1 reverse transcriptase (RT-1). An azido photoaffinity analogue of BI-RG-587 was synthesized and found to irreversibly inhibit the enzyme upon UV irradiation. BI-RG-587 and close structural analogues competitively protected RT-1 from inactivation by the photoaffinity label. A thiobenzimidazolone (TIBO) derivative, a nonnucleoside inhibitor of RT-1, also protected the enzyme from photoinactivation, which suggests a common binding site for these compounds. Substrates dGTP, template-primer, and tRNA afforded no protection from enzyme inactivation. A tritiated photoaffinity probe was found to stoichiometrically and selectively label p66 such that 1 mol of probe inactivates 1 mol of RT-1.
Wu
J C
JC
Department of Biochemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
Warren
T C
TC
Adams
J
J
Proudfoot
J
J
Skiles
J
J
Raghavan
P
P
Perry
C
C
Potocki
I
I
Farina
P R
PR
Grob
P M
PM
D000345:Affinity Labels / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000378:metabolism; D019829:Nevirapine; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D000345:Affinity Labels; D000998:Antiviral Agents; D001798:Blood Proteins; D011725:Pyridines; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D012194:RNA-Directed DNA Polymerase