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Antimicrobial Agents and Chemotherapy, January 2001, p. 158-165, Vol. 45, No. 1
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-beta -D-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-beta -D-Dioxolane Guanosine

Phillip A. Furman,1,* Jerry Jeffrey,1 Laura L. Kiefer,1 Joy Y. Feng,1 Karen S. Anderson,2 Katyna Borroto-Esoda,1 Edgar Hill,1 William C. Copeland,3 Chung K. Chu,4 Jean-Pierre Sommadossi,5 Irina Liberman,6 Raymond F. Schinazi,6 and George R. Painter1

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

(-)-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 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 alpha  and beta . Against the large subunit of human DNA polymerase gamma  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.

Antimicrobial Agents and Chemotherapy, January 2001, p. 158-165, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.158-165.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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