Mechanism of action of 1-beta-D-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus type 1 inhibitor 1-beta-D-dioxolane guanosine

Antimicrob Agents Chemother. 2001 Jan;45(1):158-65. doi: 10.1128/AAC.45.1.158-165.2001.


(-)-beta-D-2,6-Diaminopurine dioxolane (DAPD), is a nucleoside reverse transcriptase (RT) inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). DAPD, which was designed as a water-soluble prodrug, is deaminated by adenosine deaminase to give (-)-beta-D-dioxolane guanine (DXG). By using calf adenosine deaminase a K(m) value of 15 +/- 0.7 microM was determined for DAPD, which was similar to the K(m) value for adenosine. However, the k(cat) for DAPD was 540-fold slower than the k(cat) for adenosine. In CEM cells and peripheral blood mononuclear cells exposed to DAPD or DXG, only the 5'-triphosphate of DXG (DXG-TP) was detected. DXG-TP is a potent alternative substrate inhibitor of HIV-1 RT. Rapid transient kinetic studies show the efficiency of incorporation for DXG-TP to be lower than that measured for the natural substrate, 2'-deoxyguanosine 5'-triphosphate. DXG-TP is a weak inhibitor of human DNA polymerases alpha and beta. Against the large subunit of human DNA polymerase gamma a K(i) value of 4.3 +/- 0.4 microM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Deaminase Inhibitors
  • Anti-HIV Agents / pharmacology*
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / microbiology
  • Cells, Cultured
  • DNA, Viral / biosynthesis
  • Dioxolanes / pharmacology*
  • Drug Resistance, Microbial
  • Enzyme Inhibitors / pharmacology
  • Guanosine / analogs & derivatives*
  • Guanosine / pharmacology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / ultrastructure
  • Humans
  • Lactic Acid / metabolism
  • Microscopy, Electron
  • Mitochondria / drug effects
  • Nucleic Acid Synthesis Inhibitors
  • Prodrugs / pharmacology*
  • Purine Nucleosides / pharmacology*
  • Reverse Transcriptase Inhibitors / pharmacology*


  • Adenosine Deaminase Inhibitors
  • Anti-HIV Agents
  • DNA, Viral
  • Dioxolanes
  • Enzyme Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Prodrugs
  • Purine Nucleosides
  • Reverse Transcriptase Inhibitors
  • dioxolane guanosine
  • Guanosine
  • Lactic Acid
  • amdoxovir