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Antiviral effect of -glucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles

¹ INSERM U271, Laboratoire des Virus Hépatiques et Pathologies Associées, 151 cours Albert Thomas, 69424 Lyon Cedex 03, France
² INSERM ESPRI 3856, Université François Rabelais, Tours, France
³ Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK
⁴ CNRS-UPR2511, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France

Correspondence
David Durantel
durantel{at}lyon.inserm.fr

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. -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 -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 -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 -glucosidase inhibitors, these VLPs contain unprocessed, triglucosylated N-glycans and potentially misfolded glycoproteins. Finally, it is demonstrated that VLPs produced in the presence of -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 -glucosidase inhibitors may prove to be useful molecules to fight HCV infection in combination protocols.

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