This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Matthes, E. Articles by Sirma, H. Search for Related Content PubMed PubMed Citation Articles by Matthes, E. Articles by Sirma, H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2007, p. 2523-2530, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00001-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N⁴-Hydroxy- and 5-Methyl-β-L-Deoxycytidine Analogues

E. Matthes,^1*, A. Funk,^2, I. Krahn,¹ K. Gaertner,¹ M. von Janta-Lipinski,¹ L. Lin,^2, H. Will,² and H. Sirma²

Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13092 Berlin,¹ Heinrich-Pette-Institut für Experimentelle Immunologie und Virologie, P.O. Box 201652, 20251 Hamburg, Germany²

Received 2 January 2007/ Returned for modification 12 February 2007/ Accepted 21 March 2007

Novel N⁴-hydroxy- and 5-methyl-modified β-L-deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiencies were investigated in HepG2.2.15 cells stably transfected with HBV. β-L-2',3'-Didehydro-2',3'-dideoxy-N⁴-hydroxycytidine (β-L-Hyd4C) was most effective in reducing secreted HBV DNA (50% effective concentration [EC₅₀], 0.03 µM), followed by β-L-2',3'-dideoxy-3'-thia-N⁴-hydroxycytidine (EC₅₀, 0.51 µM), β-L-2',3'-dideoxy-N⁴-hydroxycytidine (EC₅₀, 0.55 µM), and β-L-5-methyl-2'-deoxycytidine (EC₅₀, 0.9 µM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the β-L-cytidine derivatives was also assessed. In accordance with the cell culture data, β-L-Hyd4C triphosphate was the most active inhibitor, with a 50% inhibitory concentration of 0.21 µM. The cytotoxicities of some of the 4-NHOH-modified β-L-nucleosides were dramatically lower than those of the corresponding cytidine analogues with the unmodified 4-NH₂ group. The 50% cytotoxic concentrations for β-L-Hyd4C in HepG2 and HL-60 cells were 2,500 µM and 3,500 µM, respectively. In summary, our results demonstrate that at least β-L-Hyd4C can be recommended as a highly efficient and extremely selective inhibitor of HBV replication for further investigations.

---

* Corresponding author. Mailing address: Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Str. 10, 13092 Berlin, Germany. Phone: 49 30 9406 3409. Fax: 49 30 9406 3138. E-mail: emat{at}mdc-berlin.de

Published ahead of print on 2 April 2007.

E.M. and A.F. contributed equally to this work.

Present address: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033.

---

Antimicrobial Agents and Chemotherapy, July 2007, p. 2523-2530, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00001-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.