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

Journal Article · Tue Feb 26 00:00:00 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), Vol. 30:8; ISSN 0006-2960
• Country of Publication: United States
• Language: English

Related Subjects

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