Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro

Yokota, Tomoyuki; Konno, Kenji; Chonan, E; Mochizuki, S; Kojima, Kana; Shigeta, Shirô; Clercq, Erik De

doi:10.1128/aac.34.7.1326

Cited by 71 publications

(42 citation statements)

References 23 publications

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“…Several other purine nucleoside analogs have already been reported to inhibit hepadnavirus replication both in vitro and in vivo (12,17,28,35). Ganciclovir, in particular, is known to inhibit replication of ground squirrel HBV (26), human HBV (20), and DHBV (23,33,34) in vivo and in vitro (8,34).…”

Section: Discussionmentioning

confidence: 99%

In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus

Shaw

Amor

Civitico

et al. 1994

Antimicrob Agents Chemother

101

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The in vitro antihepadnavirus activities of the purine nucleoside analogs ganciclovir {9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine} and penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] were compared in primary duck hepatocyte cultures congenitally infected with the duck hepatitis B virus (DHBV). Both compounds inhibited DHBV DNA replication to a comparable extent during continuous short-term treatment of the cultures. However penciclovir was more active both during longer-term continuous treatment (50% inhibitory concentrations: penciclovir, 0.7 ± 0.1 ,uM; ganciclovir, 4.0 ± 0.2 ,uM) and in washout experiments (50% inhibitory concentrations: penciclovir, 3.0 ± 0.4 ,uM; ganciclovir, 46 ± 1.5 ,uM) designed to compare the persistence of inhibitory activity after removal of the extracellular compound. The effects on viral protein synthesis were similar to the effects on viral DNA replication. These data suggest that penciclovir or its oral form, famciclovir, may have clinical utility in the treatment of chronic hepatitis B virus infection.Attempts to develop therapy against hepatitis B virus (HBV) have been hampered by its extremely narrow host range (only humans and chimpanzees are susceptible to HBV infection) and by the inability of cell lines to support complete autonomous HBV replication (22). These problems have been overcome to some extent by the recent development of assay systems for identifying potential antihepadnavirus agents. Animal models of HBV infection, particularly those of the woodchuck and duck, have been used for in vivo testing and evaluation, while continuous HBV-transfected cell lines and primary hepatocytes have been used for in vitro screening. The utilities and validities of these systems seem to have been vindicated by findings that agents previously found to be active in clinical studies (2,19,20) are generally active in the test systems (8,21,23,33,34) MATERLILS AND METHODSAnimals. One-day-old Pekin-Aylesbury cross ducks congenitally infected with an Australian strain of DHBV were obtained from a commercial supplier (33). Viremia was monitored by dot blot hybridization of serum, and 7-to 14-day-old ducklings with stable viral titers of 5 x 108 to 10 x 108 viral genome equivalents per ml were selected for hepatocyte isolation.Cell culture. Primary cultures of duckling hepatocytes were prepared as described previously (5, 30), except that feeder cell layers (a potential source of competing nucleosides) were not used. Six-well plastic culture plates (Greiner, Frickenhausen, Germany) were seeded with 2 x 106 to 2.5 x 106 hepatocytes per well, and cells were allowed to attach overnight before the first medium change (on day 1 postplating) and were maintained with medium changes every second day. Antiviral drug treatment. For each experiment, triplicate sets of PDH monolayers were exposed to drug concentrations in the range 0 to 500 ,uM beginning on day 1 postplating. One set was harvested after 5 days of drug treatment. Treatment of the second set was stopped aft...

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Section: Discussionmentioning

confidence: 99%

In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus

Shaw

Amor

Civitico

et al. 1994

Antimicrob Agents Chemother

101

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“…Because adefovir, like cidofovir, has low oral bioavailability, its bis(pivaloyloxymethyl) ester (adefovir dipivoxil) was further developed (80,81). Adefovir dipivoxil was originally pursued as a potential anti-HIV drug, but it was eventually abandoned for this purpose for a number of reasons: (a) At the dosage (125 mg daily) needed to be effective against HIV, it proved nephrotoxic upon prolonged administration (>6 months); (b) tenofovir, which had just come along, proved at least as potent against HIV and clearly less nephrotoxic; and (c) adefovir, going back to the original observations of Yokota et al (82,83) and Heijtink et al (84,85), turned out to be effective against hepatitis B virus (HBV) at a much lower dose (10 mg daily) than was needed for HIV. Thus adefovir dipivoxil was successfully launched at a dose of 10 mg per day for the treatment of HBV (86,87).…”

Section: The Acyclic Nucleoside Phosphonatesmentioning

confidence: 99%

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

Clercq

2011

Annu. Rev. Pharmacol. Toxicol.

147

144

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My search for a selective antiviral chemotherapy started more than 40 years ago with interferon inducers, then shifted to nucleoside analogs with the discovery of BVDU (brivudin), a highly selective anti-HSV-1 and anti-VZV agent, and to dideoxynucleoside analogs such as d4T (stavudine), anti-HIV agents. The search culminated in the discovery of acyclic nucleoside phosphonates (ANPs) (in collaboration with Antonin Holý), a key class of compounds active against HIV, hepatitis B virus, and DNA viruses at large; the best known of these compounds is tenofovir. Along the way, the principle of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was established. This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an "ideal" NNRTI.1

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“…These compounds were also found to inhibit duck hepatitis B virus (DHBV) core antigen synthesis in primary duck hepatocytes (Yokota et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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

Yokota¹,

Konno²,

Shigeta

et al. 1994

Antivir Chem Chemother

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SummaryBy 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 -phosphonylmethoxyethyQ -1 -deazaadenine (PMEC 1A), 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 phosphonates (i.e. PMEA, PMEDAP, HPMPA) were prepared. They proved inhibitory to HBV DNA polymerase but not cellular DNA polymerase ct.

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Comparative activities of several nucleoside analogs against duck hepatitis B virus in vitro

Cited by 71 publications

References 23 publications

In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus

In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

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

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