| Autor: |
Furman, Phillip A., Jeffrey, Jerry, Kiefer, Laura L., Feng, Joy Y., Anderson, Karen S., Borroto-Esoda, Katyna, Hill, Edgar, Copeland, William C., Chu, Chung K., Sommadossi, Jean-Pierre, Liberman, Irina, Schinazi, Raymond F., Painter, George R. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; January 2001, Vol. 45 Issue: 1 p158-165, 8p |
| Abstrakt: |
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 Kmvalue of 15 ± 0.7 μM was determined for DAPD, which was similar to theKmvalue for adenosine. However, thekcatfor DAPD was 540-fold slower than thekcatfor 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 aKivalue 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. |
| Databáze: |
Supplemental Index |
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