title: Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release.
abstract: 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.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902, USA.
authors.forename: Xiaowang
authors.initials: X
authors.lastname: Qu
authors.forename: Xiaoben
authors.initials: X
authors.lastname: Pan
authors.forename: Jessica
authors.initials: J
authors.lastname: Weidner
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.forename: Dominic
authors.initials: D
authors.lastname: Alonzi
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.forename: Terry
authors.initials: T
authors.lastname: Butters
authors.forename: Timothy
authors.initials: T
authors.lastname: Block
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D014771:Virion / Q000187:drug effects*; D019065:Virus Assembly / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors