(-)-Beta-D-1',3'-Dioxolane
guanosine (
DXG) and
2,6-diaminopurine (DAPD) dioxolanyl
nucleoside analogues have been reported to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1). We have recently conducted experiments to more fully characterize their in vitro anti-HIV-1 profiles.
Antiviral assays performed in cell culture systems determined that
DXG had 50% effective concentrations of 0.046 and 0.085 microM when evaluated against HIV-1(IIIB) in cord blood mononuclear cells and MT-2 cells, respectively. These values indicate that
DXG is approximately equipotent to 2', 3'-dideoxy-3'-thiacytidine (3TC) but 5- to 10-fold less potent than
3'-azido-2',3'-dideoxythymidine (AZT) in the two cell systems tested. At the same time, DAPD was approximately 5- to 20-fold less active than
DXG in the anti-HIV-1 assays. When recombinant or clinical variants of HIV-1 were used to assess the efficacy of the
purine nucleoside analogues against
drug-resistant HIV-1, it was observed that AZT-resistant virus remained sensitive to
DXG and DAPD. Virus harboring a mutation(s) which conferred decreased sensitivity to 3TC,
2',3'-dideoxyinosine, and
2',3'-dideoxycytidine, such as a 65R, 74V, or 184V mutation in the viral
reverse transcriptase (RT), exhibited a two- to fivefold-decreased susceptibility to
DXG or DAPD. When nonnucleoside RT inhibitor-resistant and
protease inhibitor-resistant viruses were tested, no change in virus sensitivity to
DXG or DAPD was observed. In vitro
drug combination assays indicated that
DXG had synergistic
antiviral effects when used in combination with AZT, 3TC, or
nevirapine. In cellular toxicity analyses,
DXG and DAPD had 50% cytotoxic concentrations of greater than 500 microM when tested in peripheral blood mononuclear cells and a variety of human
tumor and normal cell lines. The
triphosphate form of
DXG competed with the natural
nucleotide substrates and acted as a chain terminator of the nascent
DNA. These data suggest that
DXG triphosphate may be the active intracellular metabolite, consistent with the mechanism by which other
nucleoside analogues inhibit HIV-1 replication. Our results suggest that the use of
DXG and DAPD as therapeutic agents for HIV-1
infection should be explored.