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

Matthes, E., Funk, A., Krahn, I., Gaertner, K., von Janta-Lipinski, M., Lin, L., Will, H. and Sirma, H. (2007) Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-β-L-Deoxycytidine Analogues{triangledown}. Antimicrobial agents and chemotherapy, 51 7: 2523-2530. doi:10.1128/AAC.00001-07

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Author Matthes, E.
Funk, A.
Krahn, I.
Gaertner, K.
von Janta-Lipinski, M.
Lin, L.
Will, H.
Sirma, H.
Title Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-β-L-Deoxycytidine Analogues{triangledown}
Journal name Antimicrobial agents and chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2007
Sub-type Article (original research)
DOI 10.1128/AAC.00001-07
Open Access Status File (Publisher version)
Volume 51
Issue 7
Start page 2523
End page 2530
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Subject 060506 Virology
Abstract 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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