The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds

Abstract MKC-442, a derivative of the non-nucleoside reverse transcriptase (RT) inhibitor 1-[(2-hydroxyethoxy)methyl)-6-(phenylthio)thymidine (HEPT), showed potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro, using a range of host-cell/virus systems including human peripheral blood mononuclear cells infected with primary clinical isolates. MKC-442 was evaluated in combination with the nucleoside analogues AZT, ddI and ddC, the non-nucleoside RT inhibitor nevirapine, the HIV-1 proteinase inhibitor Ro-31-8959, and the α-glucosidase 1 inhibitor, MDL-28,574, using a cell viability assay. Drug interactions were evaluated by the isobologram technique and by calculating combination indices. Notable synergistic inhibition of HIV-1 replication was observed when MKC-442 was combined with AZT and MDL-28,574 and moderate synergy with ddI. In combination with ddC, nevirapine or Ro-31-8959, only a slightly better than additive effect was observed. Impressive synergy was seen using the three-drug combinations of MKC-442, AZT and MDL-28,574 or MKC-442, AZT and Ro-31-8959. No additional cytotoxicity was observed as measured by [ 3 H]thymidine incorporation by concanavalin A-stimulated peripheral blood mononuclear cells, when MKC-442 was combined with any of the above-mentioned compounds. The use of MKC-442 in a two- or three-drug combination regimen with other RT inhibitors, a proteinase inhibitor or an α-glucosidase 1 inhibitor should be considered for HIV-1-related chemotherapy.