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Antimicrobial Agents and Chemotherapy, July 1998, p. 1805-1810, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Anti-Hepatitis B Virus Activity and Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine

Yong-Lian Zhu,dagger Ginger E. Dutschman, Shwu-Huey Liu, Edward G. Bridges, and Yung-Chi Cheng*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

Received 14 November 1997/Returned for modification 7 March 1998/Accepted 9 April 1998

2',3'-Dideoxy-2',3'-didehydro-beta -L(-)-5-fluorocytidine [L(-)Fd4C] was found to be at least 10 times more potent than beta -L-2',3'-dideoxy-3'-thiacytidine [L(-)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of L(-)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations up to 10 µM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with L(-)Fd4C than with L(-)SddC (3TC). L(-)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of L(-)Fd4C phosphorylation to the 5'-triphosphate metabolite was higher than the degree of L(-)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparent Km of L(-)Fd4C phosphorylated metabolites formed intracellularly was higher than that for L(-)SddC (3TC). This may be due in part to a difference in the behavior of L(-)Fd4C and L(-)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, L(-)Fd4C 5'-triphosphate was retained longer within cells than L(-)SddC (3TC) 5'-triphosphate. L(-)Fd4C 5'-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a Ki of 0.069 ± 0.015 µM. Given the antiviral potency and unique pharmacodynamic properties of L(-)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., P.O. Box 802066, New Haven, CT 06520-8066. Phone: (203) 785-7118. Fax: (203) 785-7129. E-mail: cheng.lab{at}yale.edu.

dagger Present address: Department of Pharmacology, Zhejiang Medical University, Hangzhou, Zhejiang 310006, People's Republic of China.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1805-1810, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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