Anti-hepatitis B virus activity and metabolism of 2′,3′-dideoxy-2′,3′-didehydro-β-L(-)-5-fluorocytidine

被引：43
|
作者：
Zhu, YL [1 ]
Dutschman, GE [1 ]
Liu, SH [1 ]
Bridges, EG [1 ]
Cheng, YC [1 ]
机构：
[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
来源：
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 1998年 / 42卷 / 07期
关键词：
D O I：
10.1128/AAC.42.7.1805
中图分类号：
Q93 [微生物学];
学科分类号：
071005 ; 100705 ;
摘要：
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 mu M 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 K-m 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 K-i of 0.069 +/- 0.015 mu M. 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.
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页码：1805 / 1810
页数：6
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