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Mechanism of Action of 1-β- d -2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β- d -Dioxolane Guanosine

2001; American Society for Microbiology; Volume: 45; Issue: 1 Linguagem: Inglês

10.1128/aac.45.1.158-165.2001

1098-6596

Phillip A. Furman, Jerry Jeffrey, Laura L. Kiefer, Joy Y. Feng, Karen S. Anderson, Katyna Borroto–Esoda, Edgar L. Hill, William C. Copeland, Chung K. Chu, Jean‐Pierre Sommadossi, Irina Liberman, Raymond F. Schinazi, George R. Painter,

Cytomegalovirus and herpesvirus research

ABSTRACT (−)-β- 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 (−)-β- d -dioxolane guanine (DXG). By using calf adenosine deaminase a K m value of 15 ± 0.7 μM 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 α and β. Against the large subunit of human DNA polymerase γ a K i value of 4.3 ± 0.4 μM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.