Metabolism and Mode of Inhibition of Varicella-Zoster Virus byl-β-5-Bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil Is Dependent on Viral Thymidine Kinase
- Ling Li1,
- Ginger E. Dutschman1,
- Elizabeth A. Gullen1,
- Eisaku Tsujii1,
- Susan P. Grill1,
- Yongseok Choi2,
- Chung K. Chu2 and
- Yung-chi Cheng
- 1Department of Pharmacology, Yale University, New Haven, Connecticut (L.L., G.E.D., E.A.G., E.T., S.P.G., Y.-c.C.); and 2College of Pharmacy, University of Georgia, Athens, Georgia (Y.C., C.K.C.)
Abstract
A nonnaturally occurring l-configuration nucleoside analog,l-β-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (l-BVOddU) selectively inhibited varicella-zoster virus growth in human embryonic lung (HEL) 299 cell culture with an EC50 of 0.055 μM, whereas no inhibition of CEM and HEL 299 cell growth or mitochondrial DNA synthesis was observed at concentrations up to 200 μM. l-BVOddU was phosphorylated by viral thymidine kinase but not by human cytosolic thymidine kinase, and the antiviral activity of this compound is dependent on the viral thymidine kinase. Unlike other d-configuration bromovinyl deoxyuridine analogs, such as E-5-(2-bromovinyl)-2′-deoxyuridine and 1-β-arabinofuranosyl-E-5-(2-bromovinyl)uracil, this compound was metabolized only to its monophosphate metabolite. The di- or triphosphate metabolites were not detected. This suggested that the inhibitory mechanism may be unique and different from other anti-herpesvirus nucleoside analogs.
Footnotes
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Send reprint requests to: Yung-chi Cheng, SHM-B 315, Department of Pharmacology, Yale University, New Haven, CT 06520. E-mail: Cheng_lab{at}yale.edu
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This study was supported by National Institutes of Health grants CA 63477 and AI 33655. Y.-C. Cheng is a fellow of the National Foundation for Cancer Research.
- Abbreviations:
- d-BVDU
- (E)-5-(2-bromovinyl)-2′-deoxyuridine
- VZV
- varicella-zoster virus
- EBV
- Epstein-Barr virus
- l-BVOddU
- l-β-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil
- l-BVDU
- l-(E)-5-(2-bromovinyl)-2′-deoxyuridine
- d-BVOddU
- d-β-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil
- BV-araU
- 1-β-arabinofuranosyl-E-5-(2-bromovinyl)uracil
- ACV
- acyclovir
- TK
- thymidine kinase
- HSV
- herpes simplex virus
- dThd
- thymidine
- 5′-Et dThd
- 5′-ethynyl thymidine
- HEL 299
- human embryonic lung cell
- DPD
- dihydropyrimidine dehyrogenase
- RT
- retention time
- 5-FU
- 5-fluorouracil
- DTT
- dithiothreitol
- HPLC
- high-performance liquid chromatography
- BVU
- bromovinyl uracil
- l-BVOddUMP
- l-BVOddU monophosphate
- d-BVDUTP
- d-BVDU triphosphate
- d-BVDUMP
- d-BVDU monophosphate
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- Received May 12, 2000.
- Accepted July 18, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
