Inhibitory Effects of Acyclic Nucleoside Phosphonate Analogues on Hepatitis B Virus DNA Synthesis in HB611 Cells

1994 ◽  
Vol 5 (2) ◽  
pp. 57-63 ◽  
Author(s):  
T. Yokota ◽  
K. Konno ◽  
S. Shigeta ◽  
A. Holy ◽  
J. Balzarini ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Hbv Dna ◽  
Inhibitory Effects ◽  
B Virus ◽  
Acyclic Nucleoside ◽  
Cellular Dna ◽  
Acyclic Nucleoside Phosphonate

By using an assay system based on a human hepatoblastoma cell line (HB611) that continuously synthesizes hepatitis B virus (HBV) DNA, 56 acyclic nucleoside phosphonate analogues were examined for their inhibitory effects on HBV DNA synthesis. The following compounds were found to inhibit HBV DNA synthesis at concentrations that were significantly lower than their minimum cytotoxic concentrations; 9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxyethyl) guanine(PMEG), 9-(2-phosphonylmethoxyethyl) guanine ethyl ester (PMEGEE), 9 - (2 - phosphonylmethoxyethyl) - 1 - deazaadenine (PMEC1A), 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), ( S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), 9-(3-isopropoxy-2-phosphonylmethoxypropyl)adenine (IPPMPA), 9-( RS)-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(3-hydroxy-2-phosphonylmethoxypropyl)-2, 6-diaminopurine (HPMPDAP). The most selective compounds (with indexes greater than 100) were PMEDAP, PMEA, IPPMPA, and PMPA. Acyclic pyrimidine nucleoside phosphonate analogues did not prove markedly selective as anti-HBV agents. Diphosphoryl derivatives of some acyclic purine nucleoside phos-phonates (i.e. PMEA, PMEDAP, HPMPA) were prepared. They proved inhibitory to HBV DNA polymerase but not cellular DNA polymerase α.

scholarly journals Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis.

1991 ◽  
Vol 35 (2) ◽  
pp. 394-397 ◽  
Author(s):  
T Yokota ◽  
S Mochizuki ◽  
K Konno ◽  
S Mori ◽  
S Shigeta ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Inhibitory Effects ◽  
Hepatitis B Virus Dna ◽  
Antiviral Compounds ◽  
Human Hepatitis ◽  
B Virus

scholarly journals Inhibition of replication of hepatitis B virus by cytallene in vitro.

1997 ◽  
Vol 41 (8) ◽  
pp. 1755-1760 ◽  
Author(s):  
Y L Zhu ◽  
S B Pai ◽  
S H Liu ◽  
K L Grove ◽  
B C Jones ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Culture Medium ◽  
Hbv Dna ◽  
Inhibition Concentration ◽  
B Virus ◽  
Mitochondrial Dna Synthesis ◽  
Potent Inhibitory Activity

The acyclic cytosine nucleoside analog cytallene [1-(4'-hydroxy-1',2'-butadienyl)cytosine], which has both (+)- and (-)-enantiomers, was evaluated for its anti-hepatitis B virus (HBV) activity in 2.2.15 cells and was found to have potent activity against HBV DNA synthesis. The R-(-)-enantiomer was found to be the more active of the cytallene enantiomers, with a 50% inhibition concentration against HBV synthesis (HBIC50) of 0.08 microM. Its antiviral activity could be reversed by deoxycytidine (dC) and less efficiently by cytidine. Upon removal of the R-(-)-enantiomer from culture medium, the synthesis of HBV DNA could reinitiate, which suggested that the antiviral action is reversible. The R-(-)-enantiomer was also found to be more cytotoxic than the S-(+)-enantiomer. The degree of cytotoxicity varied among the cell lines, with a 50% inhibition of cell growth at greater than 10 microM. The R-(-)-enantiomer had no effect on HBV RNA synthesis and mitochondrial DNA synthesis at a concentration of 10 times or more than the HBIC50. The two enantiomers cannot be deaminated by dC deaminase, and they can be phosphorylated by cytoplasmic dC kinase. The R-(-)-enantiomer of cytallene is the first acyclic cytosine analog with potent inhibitory activity against HBV similar to those of other L-(-)-ddC analogs.

Effect of hepatocyte proliferation and cellular DNA synthesis on hepatitis B virus replication

1996 ◽  
Vol 110 (5) ◽  
pp. 1519-1528 ◽  
Author(s):  
A Ozer ◽  
VI Khaoustov ◽  
M Mearns ◽  
DE Lewis ◽  
RM Genta ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Virus Replication ◽  
Hepatocyte Proliferation ◽  
B Virus ◽  
Cellular Dna

scholarly journals Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

2021 ◽  
Author(s):  
Vladimir Reinharz ◽  
Yuji Ishida ◽  
Masataka Tsuge ◽  
Karina Durso-Cain ◽  
Tje Lin Chung ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Adaptive Immune Response ◽  
Pegylated Interferon ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Interferon Α ◽  
B Virus

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during 14-day pegylated interferon-α-2a (pegIFN), LAM or pegIFN+LAM treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the 1st phase represents inhibition of intracellular HBV DNA synthesis and secretion which was similar under all treatments with overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN + LAM (1.28/d) and the slowest (0.1/d) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production, but rather enhanced 2nd phase decline providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV. Importance Chronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamics of HBV infection and treatment response at the molecular level could facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV inhibition kinetics under pegylated interferon-α (pegIFN) in this model system have not been determined in sufficient detail. In this study, viral kinetics in 39 humanized mice treated with pegIFN and/or lamivudine were monitored and analyzed using a mathematical-modelling approach. We found that the main mode of action of interferon-α is blocking HBV DNA synthesis and that the majority of synthesized HBV DNA is secreted. Our study provides novel insights into HBV DNA dynamics within infected human hepatocytes.

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