Hepatitis B virus (HBV) envelope glycoproteins vary drastically in their sensitivity to glycan processing: Evidence that alteration of a single N-linked glycosylation site can regulate HBV secretion

Mehta, Anand; Lu, Xuanyong; Block, Timothy M.; Blumberg, Baruch S.; Dwek, Raymond A.

doi:10.1073/pnas.94.5.1822

Cited by 124 publications

(111 citation statements)

References 26 publications

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“…DNA was separated by electrophoresis on a 1.0% agarose gel, transferred to a nylon membrane and probed with 32 P-labeled HBV probes as described elsewhere. 10 HBV-specific bands were subsequently identified by phosphor image analysis (Bio-Rad, Hercules, CA).…”

Section: Cells and Compounds Madin Darby Bovine Kidney Cells (Mdbk)mentioning

confidence: 99%

“…The total DNA was extracted as described. 10 Twenty micrograms of DNA was digested with Hind III, resolved through a 1.2% agarose gel, and transferred to nylon membranes. Membranes were then hybridized with a 32 P-labeled probe containing the total HBV genome and developed as described elsewhere.…”

Section: Cells and Compounds Madin Darby Bovine Kidney Cells (Mdbk)mentioning

confidence: 99%

“…For example, by disrupting the calnexin-mediated folding of one or more of the HBV glycoproteins, glucosidase inhibitors prevent the formation and secretion of HBV. [7][8][9][10][11]16,17 Abbreviations: HBV, hepatitis B virus; N-butyl-DNJ, N-butyl-deoxynojirimycin; Nnonyl-DNJ, N-nonyl-deoxynojirimycin; N-nonyl-DGJ, N-nonyl-deoxygalactojirimycin; ER, endoplasmic reticulum; MDBK, madin darby bovine kidney cells; HPLC, high performance liquid chromatography; rcDNA, relaxed circular DNA; pgRNA, pregenomic RNA; IC50, concentration required to inhibit 50%.From the …”

mentioning

confidence: 99%

“…[7][8][9][10][11] The ␣-glucosidases (I and II) mediate the first steps in the glycan-processing pathway and allow for downstream glycan-processing events to occur. In addition, the actions of the ␣-glucosidases allow for interactions with the endoplasmic reticulum (ER) chaperones calnexin and calreticulin.…”

mentioning

confidence: 99%

“…For example, by disrupting the calnexin-mediated folding of one or more of the HBV glycoproteins, glucosidase inhibitors prevent the formation and secretion of HBV. [7][8][9][10][11]16,17 Previously we reported the use of the imino sugar N-nonyl-DNJ in the woodchuck model of chronic HBV infection. 11 This compound exhibited antiviral activity with no observed toxicity.…”

mentioning

confidence: 99%

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Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: Therapeutic implications

Mehta¹,

Carrouée

Conyers³

et al. 2001

Hepatology

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Previously we have shown that the imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In studying the mechanism of action of this compound, it was discovered that imino sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although Nnonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained antiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antiviral activity attributable to a function other than an impact on glycoprocessing. Hepatitis B virus (HBV) is the prototypic member of the hepadnaviradae family of viruses, which includes duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. 1 Worldwide, more than 350 million people are chronically infected with HBV and between 15% and 40% of these individuals will die, if left untreated, from serious liver diseases. 2 The major complication is the development of (primary) hepatocellular carcinoma, which causes an estimated 500,000 deaths annually. 3 Currently there is no definitive cure for chronic HBV infection; however, several FDA (United States Food and Drug Administration) approved clinical approaches have shown promise in some individuals. The first, interferon ␣, is an immunomodulator and has shown to be effective in achieving certain serologic milestones in between 7% and 40% of treated patients. 4 However, the need for parenteral administration, the poor long-term response, and the high frequency of adverse side effects makes interferon not ideal. 4 Also, the actual basis of the activity of interferon ␣ against HBV is unclear. The other FDA-approved HBV medicine is a nucleoside analogue, "3TC-lamivudine," now sold as "lamivudine/Epivir HBV." It is effective against human immunodeficiency virus, as well as HBV, and its mechanism of action is well understood: it is a competitive inhibitor of the viral reverse transcriptase. 5 Unlike interferon, it is orally available and effective in reducing viremia in almost all patients. 6 However, constitutive therapy is necessary and, unfortunately, escape mutants that have gained resistance to 3TC-lamivudine occur in 10% to 20% of those treated per year. Sadly, after 3 years of use, almost 70% of those treated were, again, viremic with HBV. 6 Although the pathogenicity of 3TC-lamivudineresistant escape mutants is uncertain, there clearly remains a need for alternatives and complements to interferon and the nucleoside analogues such as 3TC-lamivudine.N-butyl-deoxynojirimycin (N-butyl-DNJ) and N-nonyldeoxynojirimycin (N-nonyl-DNJ) are glucosidase inhibitors that have been shown to be antiviral against HBV in tissue culture and in the woodchuck model of chronic HBV infection. 7-11 The ␣-glucosidases (I and II) mediate the first steps in the glycan-processing pathway and a...

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Section: Cells and Compounds Madin Darby Bovine Kidney Cells (Mdbk)mentioning

confidence: 99%

Section: Cells and Compounds Madin Darby Bovine Kidney Cells (Mdbk)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…For example, by disrupting the calnexin-mediated folding of one or more of the HBV glycoproteins, glucosidase inhibitors prevent the formation and secretion of HBV. [7][8][9][10][11]16,17 Previously we reported the use of the imino sugar N-nonyl-DNJ in the woodchuck model of chronic HBV infection. 11 This compound exhibited antiviral activity with no observed toxicity.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: Therapeutic implications

Mehta¹,

Carrouée

Conyers³

et al. 2001

Hepatology

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Determining the Structure of Oligosaccharides N‐ and O‐Linked to Glycoproteins

Rudd

Dwek

2000

CP Protein Science

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Many proteins involved in biological events are glycosylated. A glycoprotein consists of a mixture of glycosylation variants of a single polypeptide chain, known as glycoforms. It has become clear that a detailed understanding of the roles which glycosylation plays in the biosynthesis, transport, biological function, and degradation of a glycoprotein can only be achieved when the protein and sugar(s) are viewed as an entity. Many glycoproteins can now be modeled by combining glycan sequencing data and oligosaccharide structural information with protein structural data. Pivotal to this approach is sensitive, state‐of‐the‐art oligosaccharide sequencing technology which can give a rapid insight into the glycosylation of a glycoprotein without the need for sophisticated equipment and expertise. This unit gives a detailed introduction into the analysis of glycans, and the many figures will help the user identify which type of experiment needs to be undertaken. Methods for releasing glycans from glycoproteins are followed by protocols for labeling and purifying (by HPLC) the glycans from the rest of the components. Strategies for N‐ and O‐glycan analysis are also included.

show abstract

Determining the Structure of Oligosaccharides N‐ and O‐Linked to Glycoproteins

2006

Self Cite

View full text Add to dashboard Cite

Many proteins involved in biological events are glycosylated. A glycoprotein consists of a mixture of glycosylation variants of a single polypeptide chain, known as glycoforms. It has become clear that a detailed understanding of the roles which glycosylation plays in the biosynthesis, transport, biological function, and degradation of a glycoprotein can only be achieved when the protein and sugar(s) are viewed as an entity. Many glycoproteins can now be modeled by combining glycan sequencing data and oligosaccharide structural information with protein structural data. Pivotal to this approach is sensitive, state-of-the-art oligosaccharide sequencing technology which can give a rapid insight into the glycosylation of a glycoprotein without the need for sophisticated equipment and expertise. This unit gives a detailed introduction into the analysis of glycans, and the many figures will help the user identify which type of experiment needs to be undertaken. Methods for releasing glycans from glycoproteins are followed by protocols for labeling and purifying (by HPLC) the glycans from the rest of the components. Strategies for N- and O-glycan analysis are also included.

show abstract

Hepatitis B virus (HBV) envelope glycoproteins vary drastically in their sensitivity to glycan processing: Evidence that alteration of a single N-linked glycosylation site can regulate HBV secretion

Abstract: The

Cited by 124 publications

References 26 publications

Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: Therapeutic implications

Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: Therapeutic implications

Determining the Structure of Oligosaccharides N‐ and O‐Linked to Glycoproteins

Determining the Structure of Oligosaccharides N‐ and O‐Linked to Glycoproteins

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