title: Inhibition of endoplasmic reticulum-resident glucosidases impairs severe acute respiratory syndrome coronavirus and human coronavirus NL63 spike protein-mediated entry by altering the glycan processing of angiotensin I-converting enzyme 2.
abstract: Endoplasmic reticulum (ER)-resident glucosidases I and II sequentially trim the three terminal glucose moieties on the N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most of the viral envelope glycoproteins contain N-linked glycans, inhibition of ER glucosidases with derivatives of 1-deoxynojirimycin, i.e., iminosugars, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. However, like viral envelope proteins, the cellular receptors of many viruses are also glycoproteins. It is therefore possible that inhibition of ER glucosidases not only compromises virion production but also disrupts expression and function of viral receptors and thus inhibits virus entry into host cells. Indeed, we demonstrate here that iminosugar treatment altered the N-linked glycan structure of angiotensin I-converting enzyme 2 (ACE2), which did not affect its expression on the cell surface or its binding of the severe acute respiratory syndrome coronavirus (SARS-CoV) spike glycoprotein. However, alteration of N-linked glycans of ACE2 impaired its ability to support the transduction of SARS-CoV and human coronavirus NL63 (HCoV-NL63) spike glycoprotein-pseudotyped lentiviral particles by disruption of the viral envelope protein-triggered membrane fusion. Hence, in addition to reducing the production of infectious virions, inhibition of ER glucosidases also impairs the entry of selected viruses via a post-receptor-binding mechanism.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Comunale
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sehgal
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
authors.affiliation: Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cuconati
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
authors.forename: Hanxin
authors.initials: H
authors.lastname: Lin
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA Ju-Tao.Guo@drexelmed.edu.
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D058957:Coronavirus NL63, Human / Q000187:drug effects / Q000472:pathogenicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005959:Glucosidases / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000472:pathogenicity*; D064370:Spike Glycoprotein, Coronavirus / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C585142:CM-10-18 compound; D004791:Enzyme Inhibitors; C000600715:IHVR-11029; C000600716:IHVR-17028; D050111:Imino Sugars; D064370:Spike Glycoprotein, Coronavirus; D005959:Glucosidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2