A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site
- 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
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550201* - Biochemistry- Tracer Techniques