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Antimicrobial Agents and Chemotherapy, January 2001, p. 158-165, Vol. 45, No. 1
Triangle Pharmaceuticals, Durham, North
Carolina 277071; Department of
Pharmacology, Yale School of Medicine, New Haven, Connecticut
06520-80662; Laboratory of Molecular
Genetics, National Institute of Environmental Health Sciences, Research
Triangle Park, North Carolina 277093;
Center for Drug Discovery, Department of Pharmaceutical and
Biomedical Sciences, The University of Georgia College of Pharmacy,
Athens, Georgia 306024; Department of
Clinical Pharmacology and The Liver Center, University of Alabama at
Birmingham, Birmingham, Alabama 352945; and
Department of Pediatrics, Emory University School of Medicine,
Atlanta, Georgia 30322, and Veterans Affairs Medical Center, Decatur,
Georgia 300336
Received 14 March 2000/Returned for modification 20 June
2000/Accepted 10 October 2000
(
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.158-165.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Mechanism of Action of
1-
-D-2,6-Diaminopurine Dioxolane, a Prodrug of the Human
Immunodeficiency Virus Type 1 Inhibitor
1-
-D-Dioxolane Guanosine
)-
-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 (
)-
-D-dioxolane guanine (DXG). By using calf
adenosine deaminase a Km value of 15 ± 0.7 µM was determined for DAPD, which was similar to the
Km value for adenosine. However, the
kcat for DAPD was 540-fold slower than the
kcat 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
and
. Against the large subunit of human DNA polymerase
a
Ki 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.
*
Corresponding author. Mailing address: Triangle
Pharmaceuticals, 4 University Place, 4611 University Dr., Durham, NC
27707. Phone: (919) 402-1104. Fax: (919) 493-5925. E-mail:
furmanpa{at}tripharm.com.
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