AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Furman, P. A.
Right arrow Articles by Painter, G. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Furman, P. A.
Right arrow Articles by Painter, G. R.

 Previous Article  |  Next Article 

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.


This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS

Copyright © 2001 by the American Society for Microbiology. All rights reserved.