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Antimicrobial Agents and Chemotherapy, May 2007, p. 1687-1693, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Comparison of the Phosphorylation of 4'-Ethynyl 2',3'-Dihydro-3'-Deoxythymidine with That of Other Anti-Human Immunodeficiency Virus Thymidine Analogs{triangledown}

Chih-Hung Hsu,1,4,{dagger} Rong Hu,1,{dagger} Ginger E. Dutschman,1 Guangwei Yang,1 Preethi Krishnan,1 Hiromichi Tanaka,2 Masanori Baba,3 and Yung-Chi Cheng1*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,1 School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan,2 Center for Chronic Viral Diseases, Division of Antiviral Chemotherapy, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan,3 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan4

Received 16 November 2006/ Returned for modification 22 December 2006/ Accepted 5 March 2007

Thymidine analogs, including 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-3'-deoxythymidine (D4T), are important antiretroviral agents. To exert antiretroviral activity, these analogs undergo a stepwise phosphorylation intracellularly to the active triphosphate metabolites. We previously reported that 4'-substituted D4T with an ethynyl group (i.e., 4'-ethynyl D4T) increased the anti-human immunodeficiency virus (HIV) activity and was active against multidrug-resistant HIV strains. 4'-Ethynyl D4T is a better substrate for phosphorylation by human thymidine kinase 1 than D4T is. In this report, we first studied the enzymes involved in the phosphorylation of 4'-ethynyl D4T from monophosphate to triphosphate metabolites. The 4'-ethynyl D4TMP is phosphorylated by recombinant human TMP kinase with a Km of 19 ± 4 µM and a kcat of 0.007 ± 0.001 s–1; the relative efficiency is about 9 and 15% of those of D4TMP and AZTMP, respectively. Several enzymes from crude cellular extracts, including nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, and 3-phosphoglycerate kinase, could phosphorylate 4'-ethynyl D4T-diphosphate. The relative phosphorylation efficiencies of 4'-ethynyl D4TDP were about 3 to 25% of those of D4TDP and were generally similar to those of AZTDP. In T-lymphoid cell lines, there was a preponderant accumulation of 4'-ethynyl D4TMP, suggesting that TMP kinase could be the rate-limiting enzyme in the metabolism of 4'-ethynyl D4T. Although the same enzymes are involved in the stepwise phosphorylation of thymidine analogs, their behaviors in phosphorylating metabolites of 4'-ethynyl D4T are different from those of D4T and AZT. Qualitatively, the metabolism of 4'-ethynyl D4T is more similar to that of AZT than to that of its progenitor, D4T.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, SHM B226, New Haven, CT 06520. Phone: (203) 785-7119. Fax: (203) 785-7129. E-mail: yccheng{at}yale.edu

{triangledown} Published ahead of print on 12 March 2007.

{dagger} Chih-Hung Hsu and Rong Hu contributed equally to this work.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1687-1693, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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