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.
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 alpha-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 [3H]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 alpha-glucosidase 1 inhibitor should be considered for HIV-1-related chemotherapy.
Brennan
T M
TM
MRC Collaborative Centre, London, UK.
Taylor
D L
DL
Bridges
C G
CG
Leyda
J P
JP
Tyms
A S
AS
D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D016049:Didanosine / Q000494:pharmacology; D004347:Drug Interactions; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015394:Molecular Structure; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D019258:Saquinavir; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology; D054836:Indolizidines
D000998:Antiviral Agents; D016049:Didanosine; D054303:HIV Reverse Transcriptase; D007212:Indolizines; D007546:Isoquinolines; D019829:Nevirapine; D011725:Pyridines; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D019258:Saquinavir; D014498:Uracil; D016047:Zalcitabine; D015215:Zidovudine; C070715:celgosivir; D054836:Indolizidines; C083858:emivirine