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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
Journal article   Open access   Peer reviewed

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

Xuesen Zhao, Fang Guo, Mary Ann Comunale, Anand Mehta, Mohit Sehgal, Pooja Jain, Andrea Cuconati, Hanxin Lin, Timothy M Block, Jinhong Chang, …
Antimicrobial agents and chemotherapy, v 59(1)
Jan 2015
DOI: https://doi.org/10.1128/AAC.03999-14
PMID: 25348530
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/AAC.03999-14View
Published, Version of Record (VoR) Open

Abstract

Antiviral Agents - pharmacology Spike Glycoprotein, Coronavirus - metabolism Enzyme Inhibitors - metabolism Glucosidases - antagonists & inhibitors Humans Imino Sugars - pharmacology Coronavirus NL63, Human - drug effects Coronavirus NL63, Human - pathogenicity Enzyme Inhibitors - pharmacology Endoplasmic Reticulum - metabolism SARS Virus - drug effects Host-Pathogen Interactions - drug effects Molecular Targeted Therapy Virus Internalization - drug effects SARS Virus - pathogenicity Peptidyl-Dipeptidase A - chemistry Antiviral Agents - chemistry Endoplasmic Reticulum - drug effects Enzyme Inhibitors - chemistry Peptidyl-Dipeptidase A - metabolism Imino Sugars - chemistry
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.

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Domestic collaboration
International collaboration
Web of Science research areas
Microbiology
Pharmacology & Pharmacy
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