SELECTIVE AND SYNERGISTIC INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE BY A NONNUCLEOSIDE INHIBITOR, MKC-442

In the search for 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine de rivatives, we have found 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil ( MKC-442) to be a highly potent and selective inhibitor of human immuno deficiency virus type 1 (HIV-1) reverse transcriptase (RT). The IC50 v alue of MKC-442 for HIV-1 RT was 8 nm. MKC-442 did not inhibit HIV-1 R Nase H, other RTs, or DNA polymerase alpha. Because its inhibitory pat tern showed noncompetitive inhibition with regard to nucleotide substr ates, its mode of action was considered to be allosteric inhibition. F rom the results of combination studies, MKC-442 was found to produce s ynergistic inhibition of HIV-1 RT with 3'-azido-2',3'-dideoxythymidine (AZT) 5'-triphosphate (AZT.TP). The dose of AZT - TP required for 50% inhibition was reduced to one tenth of control in the presence of a h alf dose of MKC-442. Although other allosteric inhibitors (Nevirapine, L-696,229, and R82,913) had the same specificity for enzyme inhibitio n, they did not show synergism with AZT . Tr in the combination index and synergy plot analyses. Synergistic inhibition of HIV-1 replication by MKC-442 and AZT has also been observed in HIV-1-infected MT-4 cell s. These results suggest that MKC-442 is a unique inhibitor of HIV-1 R T, and combination therapy with MKC-442 and AZT could be advantageous in the treatment of acquired immune deficiency syndrome.