Inhibitors of Endoplasmic Reticulum -Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release

Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 12/2010; 55(3):1036-44. DOI: 10.1128/AAC.01319-10
Source: PubMed


α-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent
proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of α-glucosidase
I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement
with the essential role of α-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells
with a panel of imino sugar derivatives, which are competitive inhibitors of α-glucosidases, did not affect intracellular
HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent
degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for imino
sugars with better antiviral activity, we found that a novel imino sugar, PBDNJ0804, had a superior ability to inhibit HCV
virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets
for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase
inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.

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    • "Since the human cells have a bypassing strategy for glucosidase trimming via the endomannosidase enzyme activity, it is feasible to conceive the potential low cytotoxicity of these drugs on the host cells. Celgosivir [150], PBDNJ0804-a deoxynojirimycin derivative [149], and CM-10-18 [147] are rER glucosidase I inhibitors that could show anti-C. albicans activity. "
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