title: Inhibition of HIV-1 reverse transcriptase by a quinazolinone and comparison with inhibition by pyridinones. Differences in the rates of inhibitor binding and in synergistic inhibition with nucleoside analogs.
abstract: 6-Chloro-(4S)-cyclopropyl-3,4-dihydro-4-((2-pyridyl)-ethynyl)quinazol in- 2(1H)-one (L-738,372) is representative of a novel structural class of nonnucleoside inhibitors of human immunodeficiency virus, strain 1 (HIV-1), reverse transcriptase (RT), the quinazolinones. L-738,372 is a reversible inhibitor of HIV-1 RT and is noncompetitive against dTTP with a Ki of 140 nM with poly(rA).oligo(dT) as primer-template. Mixed noncompetitive inhibition by L-738,372 was observed against poly(rC).oligo(dG) as primer-template. This quinazolinone binds to RT at a site that overlaps the binding site of other nonnucleoside inhibitors as evidenced by the ability of L-738,372 to displace bound radiolabeled L-696,229, a member of the pyridinone class of inhibitors of HIV-1 RT, from complexes of RT and primer-template. Inhibition by L-738,372 shows slow binding characteristics in reactions with all of the primer-templates employed. Synergistic inhibition of RT activity was evident in combinations of L-738,372 and any of the nucleoside analogs, azidothymidine triphosphate, dideoxyinosine triphosphate, or dideoxycytosine triphosphate. The azidothymidine-resistant form of RT (D67N, K70R, T215Y, K219Q) is inhibited by L-738,372 with 2-3-fold more potency than is the wild-type RT. Comparison of inhibition by L-738,372 with inhibition by pyridinone inhibitors reveals differences in synergistic inhibition with nucleoside analogs and in the rates of binding of the inhibitors.
authors.affiliation: Department of Biological Chemistry, Merck Research Labs, West Point, Pennsylvania 19486.
authors.forename: S S
authors.initials: SS
authors.lastname: Carroll
authors.forename: M
authors.initials: M
authors.lastname: Stahlhut
authors.forename: J
authors.initials: J
authors.lastname: Geib
authors.forename: D B
authors.initials: DB
authors.lastname: Olsen
mesh_terms: D001665:Binding Sites; D017931:DNA Primers; D004351:Drug Resistance; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D009705:Nucleosides / Q000494:pharmacology*; D011485:Protein Binding; D011728:Pyridones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D009705:Nucleosides; D011728:Pyridones; D011799:Quinazolines; D052999:Quinazolinones; D018894:Reverse Transcriptase Inhibitors; C091038:L 738372; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase