Inhibitory effect of 4-(2, 6-dichlorophenyl)-1, 2, 5-thiadiazol-3-yl-N-methyl, N-ethylcarbamate on replication of human immunodeficiency virus type 1 and the mechanism of action.
In the search for effective antiviral agents, we have found 4-(2, 6-dichlorophenyl)-1, 2, 5-thiadiazol-3-yl-N-methyl, N-ethylcarbamate (RD4-2025) to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) in vitro. The 50% effective concentration of RD4-2025 for HIV-1-induced cytopathic effect in MT-4 cells was 37 nM, yet no antiviral activity was observed against HIV-2. In HIV-1 reverse transcriptase (RT) assays, RD4-2025 inhibited both RNA-dependent and DNA-dependent DNA polymerase activities of a recombinant HIV-1 RT with 50% inhibitory concentrations of 0.11 and 3.5 microM, respectively. However, the compound did not affect the activity of human DNA polymerase alpha. Kinetic studies revealed that the inhibition was noncompetitive with respect to dGTP as the substrate and poly(C)/(dG) 12-18 as the template/primer. These results were in accordance with those of nonnucleoside RT inhibitors (NNRTIs), such as R89439 (an alpha-anilinophenylacetamide derivative) and nevirapine, indicating that RD4-2025 also belongs to the family of NNRTIs.
Ijichi
K
K
Rational Drug Design Laboratories, Fukushima, Japan.
Fujiwara
M
M
Hanasaki
Y
Y
Katsuura
K
K
Shigeta
S
S
Konno
K
K
Yokota
T
T
Baba
M
M
D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line / Q000166:cytology; D004259:DNA-Directed DNA Polymerase; D015497:HIV-1 / Q000502:physiology*; D007700:Kinetics; D012335:RNA, Ribosomal / Q000235:genetics; D013830:Thiadiazoles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D002219:Carbamates; D012335:RNA, Ribosomal; D013830:Thiadiazoles; C101751:RD 4-2025; D004259:DNA-Directed DNA Polymerase