Pure Nucleoside Enantiomers of Beta-2',3'-dideoxycytidine Analogs Are Selective Inhibitors of Hepatitis B Virus in Vitro

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 1994 Sep 1

PMID 7811039

Citations 13

Authors

R F Schinazi

G Gosselin

A Faraj

B E Korba

D C Liotta

C K Chu

C Mathe

J L Imbach

J P Sommadossi

Affiliations

Soon will be listed here.

Abstract

(-)-beta-L-2',3'-Dideoxycytidine (beta-L-DDC), (+)-beta-D-2',3'-dideoxycytidine (beta-D-DDC), (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FDDC), (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (beta-L-FTC), and (+)-beta-D-1,3-dioxolane-5-fluorocytidine (beta-D-FDOC) were evaluated for their anti-hepatitis B virus (anti-HBV) activities in HBV-transfected human liver cells (2.2.15). The order of decreasing potency for the compounds at the 90% effect level was beta-D-FDOC > beta-L-FTC > beta-L-FDDC approximately beta-L-DDC >> beta-D-DDC. Inhibition of HBV in transfected liver cells by the cytosine nucleosides was selective. The beta-L-nucleoside-5'-triphosphates were consistently more potent inhibitors of woodchuck hepatitis virus DNA polymerase than the corresponding natural beta-D-enantiomers.

Citing Articles

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Antiviral activity and pharmacokinetics of 1-(2,3-dideoxy-2-fluoro-beta-L-glyceropent-2-enofuranosyl)cytosine.

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Antiviral L-nucleosides specific for hepatitis B virus infection.

Bryant M, Bridges E, Placidi L, Faraj A, Loi A, Pierra C Antimicrob Agents Chemother. 2000; 45(1):229-35.

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Effect of oral administration of emtricitabine on woodchuck hepatitis virus replication in chronically infected woodchucks.

Korba B, Schinazi R, Cote P, Tennant B, Gerin J Antimicrob Agents Chemother. 2000; 44(6):1757-60.

PMID: 10817750 PMC: 89954. DOI: 10.1128/AAC.44.6.1757-1760.2000.

Intracellular metabolism of beta-L-2',3'-dideoxyadenosine: relevance to its limited antiviral activity.

Placidi L, Cretton-Scott E, Gosselin G, Pierra C, Schinazi R, Imbach J Antimicrob Agents Chemother. 2000; 44(4):853-8.

PMID: 10722481 PMC: 89782. DOI: 10.1128/AAC.44.4.853-858.2000.

References

Gilson R, Hawkins A, Kelly G, Gill S, Weller I . No effect of zidovudine on hepatitis B virus replication in homosexual men with symptomatic HIV-1 infection. AIDS. 1991; 5(2):217-20. DOI: 10.1097/00002030-199102000-00014. View

Korba B, Gerin J . Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication. Antiviral Res. 1992; 19(1):55-70. DOI: 10.1016/0166-3542(92)90056-b. View

Furman P, Davis M, Liotta D, Paff M, Frick L, Nelson D . The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother. 1992; 36(12):2686-92. PMC: 245529. DOI: 10.1128/AAC.36.12.2686. View

Schinazi R, McMillan A, Cannon D, Mathis R, Lloyd R, Peck A . Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother. 1992; 36(11):2423-31. PMC: 284347. DOI: 10.1128/AAC.36.11.2423. View

Shewach D, Liotta D, Schinazi R . Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2'-deoxycytidine kinase. Biochem Pharmacol. 1993; 45(7):1540-3. DOI: 10.1016/0006-2952(93)90058-5. View

Gosselin G, Mathe C, Bergogne M, Aubertin A, KIRN A, Schinazi R . Enantiomeric 2',3'-dideoxycytidine derivatives are potent human immunodeficiency virus inhibitors in cell cultures. C R Acad Sci III. 1994; 317(1):85-9. View

Kim H, Schinazi R, Shanmuganathan K, Jeong L, Beach J, Nampalli S . L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships. J Med Chem. 1993; 36(5):519-28. DOI: 10.1021/jm00057a001. View

Maddrey W . Chronic viral hepatitis: diagnosis and management. Hosp Pract (Off Ed). 1994; 29(2):117-20, 123-6, 129-32. DOI: 10.1080/21548331.1994.11442979. View

Lin T, Luo M, Liu M, Pai S, Dutschman G, Cheng Y . Antiviral activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC) and 2',3'-dideoxy-beta-L-cytidine (beta-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol. 1994; 47(2):171-4. DOI: 10.1016/0006-2952(94)90002-7. View

10.

Van Draanen N, Tisdale M, Parry N, Jansen R, Dornsife R, Tuttle J . Influence of stereochemistry on antiviral activities and resistance profiles of dideoxycytidine nucleosides. Antimicrob Agents Chemother. 1994; 38(4):868-71. PMC: 284558. DOI: 10.1128/AAC.38.4.868. View

11.

Gosselin G, Schinazi R, Sommadossi J, Mathe C, Bergogne M, Aubertin A . Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro. Antimicrob Agents Chemother. 1994; 38(6):1292-7. PMC: 188200. DOI: 10.1128/AAC.38.6.1292. View

12.

Schinazi R, Lloyd Jr R, Nguyen M, Cannon D, McMillan A, Ilksoy N . Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993; 37(4):875-81. PMC: 187791. DOI: 10.1128/AAC.37.4.875. View