title: A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site.
abstract: 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.
authors.affiliation: Department of Biochemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: J C
authors.initials: JC
authors.lastname: Wu
authors.forename: T C
authors.initials: TC
authors.lastname: Warren
authors.forename: J
authors.initials: J
authors.lastname: Adams
authors.forename: J
authors.initials: J
authors.lastname: Proudfoot
authors.forename: J
authors.initials: J
authors.lastname: Skiles
authors.forename: P
authors.initials: P
authors.lastname: Raghavan
authors.forename: C
authors.initials: C
authors.lastname: Perry
authors.forename: I
authors.initials: I
authors.lastname: Potocki
authors.forename: P R
authors.initials: PR
authors.lastname: Farina
authors.forename: P M
authors.initials: PM
authors.lastname: Grob
mesh_terms: 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
chemical_list: 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