Antiviral effect of alpha-glucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles.
Hepatitis C virus (HCV) infections are a major public-health concern. New antiviral drugs are needed urgently to complement and improve the efficacy of current chemotherapies. The morphogenesis of HCV represents an interesting, and still unexploited, novel molecular target. alpha-Glucosidase inhibitors derived from the glucose analogue deoxynojirimycin (DNJ) inhibit viral morphogenesis in cellulo via perturbation of the N-glycosylation pathway and hence the misfolding of viral glycoproteins that depend on certain N-glycans for correct folding. Due to the heavy N-glycosylation of HCV glycoproteins, it was hypothesized that such inhibitors would also affect HCV morphogenesis. To study the effect of alpha-glucosidase inhibitors on viral morphogenesis and binding properties, HCV virus-like particles (VLPs) were produced by using baculovirus loaded with HCV structural-protein genes. Here, it is demonstrated that, in the presence of these alpha-glucosidase inhibitors, viral glycoproteins synthesized and retained in the endoplasmic reticulum (i) contain unprocessed, triglucosylated N-glycans, (ii) are impaired in their interaction with calnexin and (iii) are at least partially misfolded. Moreover, it is shown that, although the production of VLPs is not affected by alpha-glucosidase inhibitors, these VLPs contain unprocessed, triglucosylated N-glycans and potentially misfolded glycoproteins. Finally, it is demonstrated that VLPs produced in the presence of alpha-glucosidase inhibitors have impaired binding properties to hepatoma cells. The inhibitors of morphogenesis studied here target steps of the HCV viral cycle that may prevent or delay viral resistance. These alpha-glucosidase inhibitors may prove to be useful molecules to fight HCV infection in combination protocols.
Chapel
Cynthia
C
INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France.
Garcia
Céline
C
INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France.
Roingeard
Philippe
P
INSERM ESPRI 3856, Université François Rabelais, Tours, France.
Zitzmann
Nicole
N
Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK.
Dubuisson
Jean
J
CNRS-UPR2511, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France.
Dwek
Raymond A
RA
Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK.
Trépo
Christian
C
INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France.
Zoulim
Fabien
F
INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France.
Durantel
David
D
INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016367:Baculoviridae; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006031:Glycosylation; D016174:Hepacivirus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D006801:Humans; D009024:Morphogenesis / Q000187:drug effects; D018411:Spodoptera; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000378:metabolism*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D014759:Viral Envelope Proteins; D015678:Viral Structural Proteins; C091015:glycoprotein E2, Hepatitis C virus