A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site

Journal Article · Mon Feb 25 23:00:00 EST 1991 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00222a003· OSTI ID:5623730

Wu, J C; Warren, T C; Adams, J; Proudfoot, J; Skiles, J; Raghavan, P; Perry, C; Potocki, I; Farina, P R; Grob, P M ^[1]

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1. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT (United States)

A novel dipyridodiazepinone, 6,11-dihydro-11-cyclopropyl-4-methyldipyrido(2,3-b:2{prime},3{prime}-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.

• OSTI ID: 5623730
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 30:8; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
DNA POLYMERASES
ELECTROMAGNETIC RADIATION
ENZYME INHIBITORS
ENZYMES
HYDROGEN COMPOUNDS
KINETICS
NUCLEIC ACIDS
NUCLEOTIDYLTRANSFERASES
ORGANIC COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
POLYMERASES
PROTEINS
RADIATION EFFECTS
RADIATIONS
REACTION KINETICS
RNA
STOICHIOMETRY
SUBSTRATES
TRANSFERASES
TRITIUM COMPOUNDS
ULTRAVIOLET RADIATION