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

6-Chloro-(4S)-cyclopropyl-3,4-dihydro 4-((2-pyridyl)-ethynyl)quinazoli n-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 K-i 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 e videnced by the ability of L-738,372 to displace bound radiolabeled L- 696,229, a member of the pyridinone class of inhibitors of HIV-I RT, f rom complexes of RT and primer-template. Inhibition by L-738,372 shows slow binding characteristics in reactions with all of the primer-temp lates employed. Synergistic inhibition of RT activity was evident in c ombinations of L-738,372 and any of the nucleoside analogs, azidothymi dine triphosphate, dideoxyinosine triphosphate, or dideoxycytosine tri phosphate. The azidothymidine-resistant form of RT (D67N, K70R, T215Y, K219Q) is inhibited by L-738,372 with 2-3-fold more potency than is t he wild-type RT. Comparison of inhibition by L-738,372 with inhibition by pyridinone inhibitors reveals differences in synergistic inhibitio n with nucleoside analogs and in the rates of binding of the inhibitor s.